Methods of treating and/or preventing actinic keratosis

ABSTRACT

The application pertains to methods of treating and/or preventing actinic keratosis, comprising administering a therapeutically effective amount of KX-01, 
     
       
         
         
             
             
         
       
     
     to a subject in need thereof.

RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.15/918,100, filed on Mar. 12, 2018 (now allowed), which claims priorityto, and the benefit of U.S. Provisional Application No. 62/469,889,filed on Mar. 10, 2017, the entire contents of which are incorporatedherein by reference.

BACKGROUND

Actinic keratosis, or solar keratosis, are scaly, crusty growths(lesions) caused by damage from the sun's ultraviolet rays. Theytypically appear on sun-exposed areas such as the face, bald scalp,lips, and the back of the hands, and are often elevated, rough intexture, and resemble warts. Most become red, but some will be tan,pink, and/or flesh-toned. If left untreated, up to ten percent ofactinic keratosis develop into squamous cell carcinoma (SCC), the secondmost common form of skin cancer. In rarer instances, actinic keratosismay also turn into basal cell carcinomas, the most common form of skincancer. It is estimated that more than 58 million Americans suffers fromactinic keratosis. The treatments for actinic keratosis includecryotherapy, surgical removal, chemical peel, photodynamic therapy,laser resurfacing, and/or drug-containing gel and creams. Due to theprevalence of actinic keratosis, and its ability to turn into skincancer if not treated properly, development of further treatments iswarranted.

SUMMARY

In one aspect, this application pertains at least in part, to a methodof treating and/or preventing actinic keratosis, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of KX-01:

In one aspect, KX-01 is administered to an affected area of the subjectat a dose from about 0.1 mg to about 10 mg.

In one aspect, KX-01 is administered to an affected area of the subjectat a dose from about 0.2 mg to about 5 mg.

In one aspect, KX-01 is administered to an affected area of the subjectat a dose from about 0.5 mg to about 2.5 mg.

In one aspect, KX-01 is administered to an affected area of the subjectat a dose of about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg,about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg,about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg,about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg,about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg,about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg,about 4 mg, or about 5 mg.

In one aspect, KX-01 is administered to an affected area of the subjectat a dose of about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg,about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg,about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg,about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg,about 2.4 mg, or about 2.5 mg.

In one aspect, KX-01 is administered to an affected area of the subjectat a dose from about 0.0003 mg/cm² to about 10 mg/cm².

In one aspect, KX-01 is administered to an affected area of the subjectat a dose from about 0.001 mg/cm² to about 0.4 mg/cm².

In one aspect, KX-01 is administered to an affected area of the subjectat a dose from about 0.005 mg/cm² to about 0.1 mg/cm²

In one aspect, KX-01 is administered to an affected area of the subjectat a dose from about 0.005 mg/cm² to about 0.02 mg/cm².

In one aspect, KX-01 is administered to an affected area of the subjectat a dose from about 0.025 mg/cm² to about 0.1 mg/cm².

In one aspect, KX-01 is administered to an affected area of the subjectat a dose of about 0.001 mg/cm², about 0.002 mg/cm², about 0.003 mg/cm²,about 0.004 mg/cm², about 0.005 mg/cm², about 0.006 mg/cm², about 0.007mg/cm², about 0.008 mg/cm², about 0.009 mg/cm², about 0.01 mg/cm², about0.02 mg/cm², about 0.03 mg/cm², about 0.04 mg/cm², about 0.05 mg/cm²,about 0.06 mg/cm², about 0.07 mg/cm², about 0.08 mg/cm², about 0.09mg/cm², about 0.1 mg/cm², about 0.15 mg/cm², about 0.2 mg/cm², about0.25 mg/cm², about 0.3 mg/cm², about 0.35 mg/cm², or about 0.4 mg/cm².

In one aspect, KX-01 is administered to an affected area of the subjectat a dose of about 0.005 mg/cm², about 0.006 mg/cm², about 0.007 mg/cm²,about 0.008 mg/cm², about 0.009 mg/cm², about 0.01 mg/cm², about 0.015mg/cm², about 0.02 mg/cm², about 0.025 mg/cm², about 0.03 mg/cm², about0.035 mg/cm², about 0.04 mg/cm², about 0.045 mg/cm², about 0.05 mg/cm²,about 0.055 mg/cm², about 0.06 mg/cm², about 0.065 mg/cm², about 0.07mg/cm², about 0.075 mg/cm², about 0.08 mg/cm², about 0.085 mg/cm², about0.09 mg/cm², about 0.095 mg/cm², or about 0.1 mg/cm².

In one aspect, the affected area of the subject is about 0.01 cm² toabout 300 cm².

In one aspect, the affected area of the subject is about 1 cm² to about200 cm², about 1 cm² to about 100 cm², about 1 cm² to about 75 cm²,about 1 cm² to about 50 cm², or about 1 cm² to about 25 cm².

In one aspect, the affected area of the subject is about 10 cm² to about200 cm², about 10 cm² to about 100 cm², about 10 cm² to about 75 cm²,about 10 cm² to about 50 cm², or about 10 cm² to about 25 cm².

In one aspect, the affected area of the subject is about 25 cm² to about200 cm², about 25 cm² to about 100 cm², about 25 cm² to about 75 cm², orabout 25 cm² to about 50 cm².

In one aspect, the affected area of the subject is about 25 cm² to about100 cm², about 25 cm² to about 90 cm², about 25 cm² to about 80 cm², orabout 25 cm² to about 70 cm², about 25 cm² to about 60 cm², about 25 cm²to about 50 cm², about 25 cm² to about 40 cm², or about 25 cm² to about30 cm².

In one aspect, the affected area of the subject is about 25 cm², about30 cm², about 35 cm², about 40 cm², about 45 cm², about 50 cm², about 55cm², about 60 cm², about 65 cm², about 70 cm², about 75 cm², about 80cm², about 85 cm², about 90 cm², about 95 cm², or about 100 cm².

In one aspect, the affected area of the subject is the skin.

In one aspect, the affected area of the subject is located at one ormore locations independently selected from the scalp, forehead, forearm,face, nose, ears, eye lids, lips, neck, arms, hands, trunk, legs, andfeet.

In one aspect, the subject has more than one affected area.

In one aspect, KX-01 is administered once a week, once every three days,once every two days, once a day, twice a day, three times a day, or fourtimes a day.

In one aspect, KX-01 is administered once a day or twice a day.

In one aspect, KX-01 is administered once a day.

In one aspect, KX-01 is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 days.

In one aspect, KX-01 is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, or 14 days.

In one aspect, KX-01 is administered for 1, 2, 3, 4, 5, 6, or 7 days.

In one aspect, KX-01 is administered for 1, 2, 3, 4 or 5 days.

In one aspect, KX-01 is administered for 1, 2, 3, 4, 5, or 6 days perweek.

In one aspect, KX-01 is administered for 2, 3, 4, 5, or 6 days per week.

In one aspect, KX-01 is administered once or twice daily continuouslyfor more than one day per week, followed by discontinuation of theadministration for the rest of the week.

In one aspect, KX-01 is administered once or twice daily every otherday.

In one aspect, KX-01 is administered once or twice daily every threedays, every four days, every five days, every six days, or every sevendays.

In one aspect, KX-01 is administered once or twice daily for two days ina row every three days, every four days, every five days, every sixdays, or every seven days.

In one aspect, KX-01 is administered once or twice daily for three daysin a row every four days, every five days, every six days, or everyseven days.

In one aspect, KX-01 is administered once or twice daily for four daysin a row every five days, every six days, or every seven days.

In one aspect, KX-01 is administered until the actinic keratosis isfully treated.

In one aspect, KX-01 is administered topically.

In one aspect, the administration of KX-01 reduces the number and/orseverity of local skin reactions or other adverse side effects in thesubject compared to other treatments of actinic keratosis.

In one aspect, the administration of KX-01 reduces the number of thesubjects that have local skin reactions or other adverse side effectscompared to other treatments of actinic keratosis.

In one aspect, the local skin reaction is selected from the groupselected from vesiculation, postulation, erosion, ulceration, redness,swelling, flaking, scaling, hard lumps, dryness, pus, and blistering.

In one aspect, the other side effect is selected from the groupconsisting of application site pain, application site pruritus,application site irritation, application site swelling, application siteburning sensation, application site infection, periorbital edema,nasopharyngitis, chills, sore throat, drooping eyes, puffy eyes,hypopigmentation, hyperpigmentation, and headache.

In one aspect, this application pertains at least in part, to KX-01 foruse (e.g., topical use) in the treatment and/or prevention of actinickeratosis. In certain aspects, KX-01 is for use at the doses, dosingschedules, and/or one or more affected area in a subject in need thereofas described herein.

In one aspect, this application pertains at least in part, to use (e.g.,topical use) of KX-01 in the treatment and/or prevention of actinickeratosis. In certain aspects, KX-01 is used at the doses, dosingschedules, and/or one or more affected area in a subject in need thereofas described herein.

In one aspect, this application pertains at least in part, to use ofKX-01 in the manufacture of a medicament for the treatment and/orprevention of actinic keratosis. In certain aspects, KX-01 is used atthe doses, dosing schedules, and/or one or more affected area in asubject in need thereof as described herein.

DESCRIPTION OF THE FIGURES

FIG. 1. Mean LSR composite scores vs. time—Phase 1 study of KX-01administered topically on the dorsal forearm. ∘ Cohort 1 (N=4): 0.5 mgKX-01 topically administered to a 25 cm² area with 4-8 typical AKlesions, daily for 3 consecutive days. ★ Cohort 2 (N=10): 2.0 mg KX-01topically administered to a 100 cm² area with 8-16 typical AK lesions,daily for 3 consecutive days. Δ Cohort 3 (N=8): 0.5 mg KX-01 topicallyadministered to a 25 cm² area with 4-8 typical AK lesions, daily for 5consecutive days. □ Cohort 4 (N=8): 2.0 mg KX-01 topically administeredto a 100 cm² area with 8-16 typical AK lesions, daily for 5 consecutivedays.

FIG. 2. Mean LSR composite scores vs. time—Phase 2a study of KX-01administered topically. 0.5 mg KX-01 topically administered to acontiguous treatment area of 25 cm² with 4-8 typical AK lesions for 3 or5 consecutive days.

FIGS. 3A and 3B. Comparison of skin reactions on forearms in patientstreated with Picato (Ingenol Mebutate)® (FIG. 3A) vs. KX-01 (FIG. 3B).

FIGS. 4A and 4B. Comparison of skin reactions on foreheads in patientstreated with Picato (Ingenol Mebutate)® (FIG. 4A) vs. KX-01 (FIG. 4B).

FIG. 5. A bar graph displaying median AK lesion counts over time (theleft bar of each pair of bars shows results from the 5-day treatment andthe right bar from the 3-day treatment).

DETAILED DESCRIPTION

The application pertains, at least in part, to a method of treatingand/or preventing actinic keratosis, comprising administering to asubject in need thereof a therapeutically effective amount of KX-01:

The application pertains, at least in part, to a method of treatingactinic keratosis comprising administering to a subject in need thereofa therapeutically effective amount of KX-01:

The application pertains, at least in part, to a method of preventingactinic keratosis comprising administering to a subject in need thereofa therapeutically effective amount of KX-01:

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.1 mg to about 10 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.2 mg to about 5 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.5 mg to about 2.5 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.1 mg to about 9 mg, from about 0.1 mg to about 8 mg, from about0.1 mg to about 7 mg, from about 0.1 mg to about 6 mg, from about 0.1 mgto about 5 mg, from about 0.1 mg to about 4 mg, from about 0.1 mg toabout 3 mg, from about 0.1 mg to about 2 mg, from about 0.1 mg to about1 mg, from about 0.1 mg to about 0.9 mg, from about 0.1 mg to about 0.8mg, from about 0.1 mg to about 0.7 mg, from about 0.1 mg to about 0.6mg, from about 0.1 mg to about 0.5 mg, from about 0.1 mg to about 0.4mg, from about 0.1 mg to about 0.3 mg, or from about 0.1 mg to about 0.2mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.2 mg to about 10 mg, from about 0.2 mg to about 9 mg, from about0.2 mg to about 8 mg, from about 0.2 mg to about 7 mg, from about 0.2 mgto about 6 mg, from about 0.2 mg to about 5 mg, from about 0.2 mg toabout 4 mg, from about 0.2 mg to about 3 mg, from about 0.2 mg to about2 mg, from about 0.2 mg to about 1 mg, from about 0.2 mg to about 0.9mg, from about 0.2 mg to about 0.8 mg, from about 0.2 mg to about 0.7mg, from about 0.2 mg to about 0.6 mg, from about 0.2 mg to about 0.5mg, from about 0.2 mg to about 0.4 mg, or from about 0.2 mg to about 0.3mg,

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.3 mg to about 10 mg, from about 0.3 mg to about 9 mg, from about0.3 mg to about 8 mg, from about 0.3 mg to about 7 mg, from about 0.3 mgto about 6 mg, from about 0.3 mg to about 5 mg, from about 0.3 mg toabout 4 mg, from about 0.3 mg to about 3 mg, from about 0.3 mg to about2 mg, from about 0.3 mg to about 1 mg, from about 0.3 mg to about 0.9mg, from about 0.3 mg to about 0.8 mg, from about 0.3 mg to about 0.7mg, from about 0.3 mg to about 0.6 mg, from about 0.3 mg to about 0.5mg, or from about 0.3 mg to about 0.4 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.4 mg to about 10 mg, from about 0.4 mg to about 9 mg, from about0.4 mg to about 8 mg, from about 0.4 mg to about 7 mg, from about 0.4 mgto about 6 mg, from about 0.4 mg to about 5 mg, from about 0.4 mg toabout 4 mg, from about 0.4 mg to about 3 mg, from about 0.4 mg to about2 mg, from about 0.4 mg to about 1 mg, from about 0.4 mg to about 0.9mg, from about 0.4 mg to about 0.8 mg, from about 0.4 mg to about 0.7mg, from about 0.4 mg to about 0.6 mg, or from about 0.4 mg to about 0.5mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.5 mg to about 10 mg, from about 0.5 mg to about 9 mg, from about0.5 mg to about 8 mg, from about 0.5 mg to about 7 mg, from about 0.5 mgto about 6 mg, from about 0.5 mg to about 5 mg, from about 0.5 mg toabout 4 mg, from about 0.5 mg to about 3 mg, from about 0.5 mg to about2 mg, from about 0.5 mg to about 1 mg, from about 0.5 mg to about 0.9mg, from about 0.5 mg to about 0.8 mg, from about 0.5 mg to about 0.7mg, or from about 0.5 mg to about 0.6 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.6 mg to about 10 mg, from about 0.6 mg to about 9 mg, from about0.6 mg to about 8 mg, from about 0.6 mg to about 7 mg, from about 0.6 mgto about 6 mg, from about 0.6 mg to about 5 mg, from about 0.6 mg toabout 4 mg, from about 0.6 mg to about 3 mg, from about 0.6 mg to about2 mg, from about 0.6 mg to about 1 mg, from about 0.6 mg to about 0.9mg, from about 0.6 mg to about 0.8 mg, or from about 0.6 mg to about 0.7mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.7 mg to about 10 mg, from about 0.7 mg to about 9 mg, from about0.7 mg to about 8 mg, from about 0.7 mg to about 7 mg, from about 0.7 mgto about 6 mg, from about 0.7 mg to about 5 mg, from about 0.7 mg toabout 4 mg, from about 0.7 mg to about 3 mg, from about 0.7 mg to about2 mg, from about 0.7 mg to about 1 mg, from about 0.7 mg to about 0.9mg, or from about 0.7 mg to about 0.8 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.8 mg to about 10 mg, from about 0.8 mg to about 9 mg, from about0.8 mg to about 8 mg, from about 0.8 mg to about 7 mg, from about 0.8 mgto about 6 mg, from about 0.8 mg to about 5 mg, from about 0.8 mg toabout 4 mg, from about 0.8 mg to about 3 mg, from about 0.8 mg to about2 mg, from about 0.8 mg to about 1 mg, or from about 0.8 mg to about 0.9mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.9 mg to about 10 mg, from about 0.9 mg to about 9 mg, from about0.9 mg to about 8 mg, from about 0.9 mg to about 7 mg, from about 0.9 mgto about 6 mg, from about 0.9 mg to about 5 mg, from about 0.9 mg toabout 4 mg, from about 0.9 mg to about 3 mg, from about 0.9 mg to about2 mg, or from about 0.9 mg to about 1 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 1 mg to about 10 mg, from about 1 mg to about 9 mg, from about 1mg to about 8 mg, from about 1 mg to about 7 mg, from about 1 mg toabout 6 mg, from about 1 mg to about 5 mg, from about 1 mg to about 4mg, from about 1 mg to about 3 mg, or from about 1 mg to about 2 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 2 mg to about 10 mg, from about 2 mg to about 9 mg, from about 2mg to about 8 mg, from about 2 mg to about 7 mg, from about 2 mg toabout 6 mg, from about 2 mg to about 5 mg, from about 2 mg to about 4mg, or from about 2 mg to about 3 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.2 mg to about 10 mg, from about 0.3 mg to about 10 mg, fromabout 0.4 mg to about 10 mg, from about 0.5 mg to about 10 mg, fromabout 0.6 mg to about 10 mg, from about 0.7 mg to about 10 mg, fromabout 0.8 mg to about 10 mg, from about 0.9 mg to about 10 mg, fromabout 1 mg to about 10 mg, from about 2 mg to about 10 mg, from about 3mg to about 10 mg, from about 4 mg to about 10 mg, from about 5 mg toabout 10 mg, from about 6 mg to about 10 mg, from about 7 mg to about 10mg, from about 8 mg to about 10 mg, or from about 9 mg to about 10 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.1 mg to about 9 mg, from about 0.2 mg to about 9 mg, from about0.3 mg to about 9 mg, from about 0.4 mg to about 9 mg, from about 0.5 mgto about 9 mg, from about 0.6 mg to about 9 mg, from about 0.7 mg toabout 9 mg, from about 0.8 mg to about 9 mg, from about 0.9 mg to about9 mg, from about 1 mg to about 9 mg, from about 2 mg to about 9 mg, fromabout 3 mg to about 9 mg, from about 4 mg to about 9 mg, from about 5 mgto about 9 mg, from about 6 mg to about 9 mg, from about 7 mg to about 9mg, or from about 8 mg to about 9 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.1 mg to about 8 mg, from about 0.2 mg to about 8 mg, from about0.3 mg to about 8 mg, from about 0.4 mg to about 8 mg, from about 0.5 mgto about 8 mg, from about 0.6 mg to about 8 mg, from about 0.7 mg toabout 8 mg, from about 0.8 mg to about 8 mg, from about 0.9 mg to about8 mg, from about 1 mg to about 8 mg, from about 2 mg to about 8 mg, fromabout 3 mg to about 8 mg, from about 4 mg to about 8 mg, from about 5 mgto about 8 mg, from about 6 mg to about 8 mg, or from about 7 mg toabout 8 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.1 mg to about 7 mg, from about 0.2 mg to about 7 mg, from about0.3 mg to about 7 mg, from about 0.4 mg to about 7 mg, from about 0.5 mgto about 7 mg, from about 0.6 mg to about 7 mg, from about 0.7 mg toabout 7 mg, from about 0.8 mg to about 7 mg, from about 0.9 mg to about7 mg, from about 1 mg to about 7 mg, from about 2 mg to about 7 mg, fromabout 3 mg to about 7 mg, from about 4 mg to about 7 mg, from about 5 mgto about 7 mg, or from about 6 mg to about 7 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.1 mg to about 6 mg, from about 0.2 mg to about 6 mg, from about0.3 mg to about 6 mg, from about 0.4 mg to about 6 mg, from about 0.5 mgto about 6 mg, from about 0.6 mg to about 6 mg, from about 0.7 mg toabout 6 mg, from about 0.8 mg to about 6 mg, from about 0.9 mg to about6 mg, from about 1 mg to about 6 mg, from about 2 mg to about 6 mg, fromabout 3 mg to about 6 mg, from about 4 mg to about 6 mg, or from about 5mg to about 6 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.1 mg to about 5 mg, from about 0.2 mg to about 5 mg, from about0.3 mg to about 5 mg, from about 0.4 mg to about 5 mg, from about 0.5 mgto about 5 mg, from about 0.6 mg to about 5 mg, from about 0.7 mg toabout 5 mg, from about 0.8 mg to about 5 mg, from about 0.9 mg to about5 mg, from about 1 mg to about 5 mg, from about 2 mg to about 5 mg, fromabout 3 mg to about 5 mg, or from about 4 mg to about 5 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.1 mg to about 4 mg, from about 0.2 mg to about 4 mg, from about0.3 mg to about 4 mg, from about 0.4 mg to about 4 mg, from about 0.5 mgto about 4 mg, from about 0.6 mg to about 4 mg, from about 0.7 mg toabout 4 mg, from about 0.8 mg to about 4 mg, from about 0.9 mg to about4 mg, from about 1 mg to about 4 mg, from about 2 mg to about 4 mg, orfrom about 3 mg to about 4 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.1 mg to about 3 mg, from about 0.2 mg to about 3 mg, from about0.3 mg to about 3 mg, from about 0.4 mg to about 3 mg, from about 0.5 mgto about 3 mg, from about 0.6 mg to about 3 mg, from about 0.7 mg toabout 3 mg, from about 0.8 mg to about 3 mg, from about 0.9 mg to about3 mg, from about 1 mg to about 3 mg, or from about 2 mg to about 3 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.1 mg to about 2 mg, from about 0.2 mg to about 2 mg, from about0.3 mg to about 2 mg, from about 0.4 mg to about 2 mg, from about 0.5 mgto about 2 mg, from about 0.6 mg to about 2 mg, from about 0.7 mg toabout 2 mg, from about 0.8 mg to about 2 mg, from about 0.9 mg to about2 mg, or from about 1 mg to about 2 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.1 mg to about 1 mg, from about 0.2 mg to about 1 mg, from about0.3 mg to about 1 mg, from about 0.4 mg to about 1 mg, from about 0.5 mgto about 1 mg, from about 0.6 mg to about 1 mg, from about 0.7 mg toabout 1 mg, from about 0.8 mg to about 1 mg, or from about 0.9 mg toabout 1 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.2 mg to about 3 mg, from about 0.2 mg to about 2.9 mg, fromabout 0.2 mg to about 2.8 mg, from about 0.2 mg to about 2.7 mg, fromabout 0.2 mg to about 2.6 mg, from about 0.2 mg to about 2.5 mg, fromabout 0.2 mg to about 2.4 mg, from about 0.2 mg to about 2.3 mg, fromabout 0.2 mg to about 2.2 mg, from about 0.2 mg to about 2.1 mg, or fromabout 0.2 mg to about 2.0 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.3 mg to about 3 mg, from about 0.3 mg to about 2.9 mg, fromabout 0.3 mg to about 2.8 mg, from about 0.3 mg to about 2.7 mg, fromabout 0.3 mg to about 2.6 mg, from about 0.3 mg to about 2.5 mg, fromabout 0.3 mg to about 2.4 mg, from about 0.3 mg to about 2.3 mg, fromabout 0.3 mg to about 2.2 mg, from about 0.3 mg to about 2.1 mg, or fromabout 0.3 mg to about 2.0 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.4 mg to about 3 mg, from about 0.4 mg to about 2.9 mg, fromabout 0.4 mg to about 2.8 mg, from about 0.4 mg to about 2.7 mg, fromabout 0.4 mg to about 2.6 mg, from about 0.4 mg to about 2.5 mg, fromabout 0.4 mg to about 2.4 mg, from about 0.4 mg to about 2.3 mg, fromabout 0.4 mg to about 2.2 mg, from about 0.4 mg to about 2.1 mg, or fromabout 0.4 mg to about 2.0 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.5 mg to about 3 mg, from about 0.5 mg to about 2.9 mg, fromabout 0.5 mg to about 2.8 mg, from about 0.5 mg to about 2.7 mg, fromabout 0.5 mg to about 2.6 mg, from about 0.5 mg to about 2.5 mg, fromabout 0.5 mg to about 2.4 mg, from about 0.5 mg to about 2.3 mg, fromabout 0.5 mg to about 2.2 mg, from about 0.5 mg to about 2.1 mg, or fromabout 0.5 mg to about 2.0 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.2 mg to about 3 mg, from about 0.3 mg to about 3 mg, from about0.4 mg to about 3 mg, from about 0.5 mg to about 3 mg, from about 0.6 mgto about 3 mg, from about 0.7 mg to about 3 mg, from about 0.8 mg toabout 3 mg, from about 0.9 mg to about 3 mg, or from about 1 mg to about3 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.2 mg to about 2.9 mg, from about 0.3 mg to about 2.9 mg, fromabout 0.4 mg to about 2.9 mg, from about 0.5 mg to about 2.9 mg, fromabout 0.6 mg to about 2.9 mg, from about 0.7 mg to about 2.9 mg, fromabout 0.8 mg to about 2.9 mg, from about 0.9 mg to about 2.9 mg, or fromabout 1 mg to about 2.9 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.2 mg to about 2.8 mg, from about 0.3 mg to about 2.8 mg, fromabout 0.4 mg to about 2.8 mg, from about 0.5 mg to about 2.8 mg, fromabout 0.6 mg to about 2.8 mg, from about 0.7 mg to about 2.8 mg, fromabout 0.8 mg to about 2.8 mg, from about 0.9 mg to about 2.8 mg, or fromabout 1 mg to about 2.8 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.2 mg to about 2.7 mg, from about 0.3 mg to about 2.7 mg, fromabout 0.4 mg to about 2.7 mg, from about 0.5 mg to about 2.7 mg, fromabout 0.6 mg to about 2.7 mg, from about 0.7 mg to about 2.7 mg, fromabout 0.8 mg to about 2.7 mg, from about 0.9 mg to about 2.7 mg, or fromabout 1 mg to about 2.7 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.2 mg to about 2.6 mg, from about 0.3 mg to about 2.6 mg, fromabout 0.4 mg to about 2.6 mg, from about 0.5 mg to about 2.6 mg, fromabout 0.6 mg to about 2.6 mg, from about 0.7 mg to about 2.6 mg, fromabout 0.8 mg to about 2.6 mg, from about 0.9 mg to about 2.6 mg, or fromabout 1 mg to about 2.6 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.2 mg to about 2.5 mg, from about 0.3 mg to about 2.5 mg, fromabout 0.4 mg to about 2.5 mg, from about 0.5 mg to about 2.5 mg, fromabout 0.6 mg to about 2.5 mg, from about 0.7 mg to about 2.5 mg, fromabout 0.8 mg to about 2.5 mg, from about 0.9 mg to about 2.5 mg, or fromabout 1 mg to about 2.5 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.2 mg to about 2.4 mg, from about 0.3 mg to about 2.4 mg, fromabout 0.4 mg to about 2.4 mg, from about 0.5 mg to about 2.4 mg, fromabout 0.6 mg to about 2.4 mg, from about 0.7 mg to about 2.4 mg, fromabout 0.8 mg to about 2.4 mg, from about 0.9 mg to about 2.4 mg, or fromabout 1 mg to about 2.4 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.2 mg to about 2.3 mg, from about 0.3 mg to about 2.3 mg, fromabout 0.4 mg to about 2.3 mg, from about 0.5 mg to about 2.3 mg, fromabout 0.6 mg to about 2.3 mg, from about 0.7 mg to about 2.3 mg, fromabout 0.8 mg to about 2.3 mg, from about 0.9 mg to about 2.3 mg, or fromabout 1 mg to about 2.3 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.2 mg to about 2.2 mg, from about 0.3 mg to about 2.2 mg, fromabout 0.4 mg to about 2.2 mg, from about 0.5 mg to about 2.2 mg, fromabout 0.6 mg to about 2.2 mg, from about 0.7 mg to about 2.2 mg, fromabout 0.8 mg to about 2.2 mg, from about 0.9 mg to about 2.2 mg, or fromabout 1 mg to about 2.2 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.2 mg to about 2.1 mg, from about 0.3 mg to about 2.1 mg, fromabout 0.4 mg to about 2.1 mg, from about 0.5 mg to about 2.1 mg, fromabout 0.6 mg to about 2.1 mg, from about 0.7 mg to about 2.1 mg, fromabout 0.8 mg to about 2.1 mg, from about 0.9 mg to about 2.1 mg, or fromabout 1 mg to about 2.1 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.2 mg to about 2 mg, from about 0.3 mg to about 2 mg, from about0.4 mg to about 2 mg, from about 0.5 mg to about 2 mg, from about 0.6 mgto about 2 mg, from about 0.7 mg to about 2 mg, from about 0.8 mg toabout 2 mg, from about 0.9 mg to about 2 mg, or from about 1 mg to about2 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose ofabout 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg,about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg,about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg,about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg,about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg,about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 4 mg, orabout 5 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose ofabout 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg,about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg,about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg,about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg,about 2.2 mg, about 2.3 mg, about 2.4 mg, or about 2.5 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose ofabout 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg,about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg,about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg,about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, orabout 2.5 mg.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.0003 mg/cm² to about 10 mg/cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.001 mg/cm² to about 0.4 mg/cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.005 mg/cm² to about 0.1 mg/cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.005 mg/cm² to about 0.02 mg/cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose fromabout 0.025 mg/cm² to about 0.1 mg/cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose ofabout 0.001 mg/cm², about 0.002 mg/cm², about 0.003 mg/cm², about 0.004mg/cm², about 0.005 mg/cm², about 0.006 mg/cm², about 0.007 mg/cm²,about 0.008 mg/cm², about 0.009 mg/cm², about 0.01 mg/cm², about 0.02mg/cm², about 0.03 mg/cm², about 0.04 mg/cm², about 0.05 mg/cm², about0.06 mg/cm², about 0.07 mg/cm², about 0.08 mg/cm², about 0.09 mg/cm²,about 0.1 mg/cm², about 0.15 mg/cm², about 0.2 mg/cm², about 0.25mg/cm², about 0.3 mg/cm², about 0.35 mg/cm², or about 0.4 mg/cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose ofabout 0.005 mg/cm², about 0.006 mg/cm², about 0.007 mg/cm², about 0.008mg/cm², about 0.009 mg/cm², about 0.01 mg/cm², about 0.015 mg/cm², about0.02 mg/cm², about 0.025 mg/cm², about 0.03 mg/cm², about 0.035 mg/cm²,about 0.04 mg/cm², about 0.045 mg/cm², about 0.05 mg/cm², about 0.055mg/cm², about 0.06 mg/cm², about 0.065 mg/cm², about 0.07 mg/cm², about0.075 mg/cm², about 0.08 mg/cm², about 0.085 mg/cm², about 0.09 mg/cm²,about 0.095 mg/cm², or about 0.1 mg/cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose ofabout 0.025 mg/cm², about 0.02 mg/cm², about 0.015 mg/cm², about 0.01mg/cm², about 0.005 mg/cm², about 0.002 mg/cm², about 0.001 mg/cm²,about 0.0005 mg/cm², about 0.0002 mg/cm², or about 0.0001 mg/cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose ofabout 0.025 mg/cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose ofabout 0.02 mg/cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose ofabout 0.015 mg/cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose ofabout 0.01 mg/cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose ofabout 0.005 mg/cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose ofabout 0.002 mg/cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose ofabout 0.001 mg/cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose ofabout 0.0005 mg/cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose ofabout 0.0002 mg/cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject at a dose ofabout 0.0001 mg/cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject that is about0.01 cm² to about 300 cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject that is about0.01 cm² to about 200 cm², about 0.01 cm² to about 100 cm², about 0.01cm² to about 75 cm², about 0.01 cm² to about 50 cm², or about 0.01 cm²to about 25 cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject that is about0.1 cm² to about 300 cm², is about 0.1 cm² to about 200 cm², about 0.1cm² to about 100 cm², about 0.1 cm² to about 75 cm², about 0.1 cm² toabout 50 cm², or about 0.1 cm² to about 25 cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject that is about 1cm² to about 300 cm², about 1 cm² to about 200 cm², about 1 cm² to about100 cm², about 1 cm² to about 75 cm², about 1 cm² to about 50 cm², orabout 1 cm² to about 25 cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject that is about10 cm² to about 300 cm², about 10 cm² to about 200 cm², about 10 cm² toabout 100 cm², about 10 cm² to about 75 cm², about 10 cm² to about 50cm², or about 10 cm² to about 25 cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject that is about25 cm² to about 300 cm², about 25 cm² to about 200 cm², about 25 cm² toabout 100 cm², about 25 cm² to about 75 cm², or about 25 cm² to about 50cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject that is theaffected area is about 25 cm² to about 100 cm², about 25 cm² to about 90cm², about 25 cm² to about 80 cm², or about 25 cm² to about 70 cm²,about 25 cm² to about 60 cm², about 25 cm² to about 50 cm², about 25 cm²to about 40 cm², or about 25 cm² to about 30 cm² In one embodiment, forany of the methods disclosed in this application, KX-01 is administeredto an affected area of the subject that is about 0.01 cm², 0.1 cm², 1cm², 2 cm², 3 cm², 4 cm², 5 cm², 6 cm², 7 cm², 8 cm², 9 cm², 10 cm², 15cm², 20 cm², 25 cm², 30 cm², 35 cm², 40 cm², 45 cm², 50 cm², 55 cm², 60cm², 65 cm², 70 cm², 75 cm², 80 cm², 85 cm², 90 cm², 95 cm², or 100 cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject that is about25 cm², about 30 cm², about 35 cm², about 40 cm², about 45 cm², about 50cm², about 55 cm², about 60 cm², about 65 cm², about 70 cm², about 75cm², about 80 cm², about 85 cm², about 90 cm², about 95 cm², or about100 cm².

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject, wherein theaffected area is the skin.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered to an affected area of the subject, wherein theaffected area of the skin is located at one or more locationsindependently selected from the scalp, forehead, forearm, face, nose,ears, eye lids, lips, neck, arms, hands, trunk, legs, and feet.

In one embodiment, for any of the methods disclosed in this application,the subject has more than one affected area.

In one embodiment, for any of the methods disclosed in this application,the subject has more than one affected area located at one or morelocations independently selected from the scalp, forehead, forearm,face, nose, ears, eye lids, lips, neck, arms, hands, trunk, legs, andfeet.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered once a week, once every three days, once every twodays, once a day, twice a day, three times a day, or four times a day.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered once a day or twice a day.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered once a day.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 days.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20 or 21 days.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or14 days.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered for 1, 2, 3, 4, 5, 6, or 7 days.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered for 1, 2, 3, 4 or 5 days.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered for 1 day.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered for 2 days.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered for 3 days.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered for 4 days.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered for 5 days.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered for 1, 2, 3, 4, 5, or 6 days per week.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered for 2, 3, 4, 5, or 6 days per week.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered once or twice daily continuously for more than oneday per week, followed by discontinuation of the administration for therest of the week.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered once or twice daily every other day.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered once or twice daily every three days, every fourdays, every five days, every six days, or every seven days.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered once or twice daily for two days in a row everythree days, every four days, every five days, every six days, or everyseven days.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered once or twice daily for three days in a row everyfour days, every five days, every six days, or every seven days.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered once or twice daily for four days in a row everyfive days, every six days, or every seven days.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered until the actinic keratosis is fully treated.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered until the actinic keratosis is fully treated,i.e., the actinic keratosis is clear from the affected area of thesubject.

In one embodiment, for any of the methods disclosed in this application,KX-01 is administered topically.

In one embodiment, for any of the methods disclosed in this application,the administration of KX-01 reduces the number and/or severity of localskin reactions or other adverse side effects in the subject compared toother treatments of actinic keratosis. In one embodiment, the othertreatment of actinic keratosis comprises the topical administration ofingenol mebutate.

In one embodiment, for any of the methods disclosed in this application,the administration of KX-01 reduces the number of the subjects that havelocal skin reactions or other adverse side effects compared to othertreatments of actinic keratosis.

In one embodiment, for any of the methods disclosed in this application,the local skin reaction is selected from the group selected fromvesiculation, postulation, erosion, ulceration, redness, swelling,flaking, scaling, hard lumps, dryness, pus, and blistering.

In one embodiment, for any of the methods disclosed in this application,the other side effect is selected from the group consisting ofapplication site pain, application site pruritus, application siteirritation, application site swelling, application site burningsensation, application site infection, periorbital edema,nasopharyngitis, chills, sore throat, drooping eyes, puffy eyes,hypopigmentation, hyperpigmentation, and headache.

In one aspect, this application pertains at least in part, to KX-01 foruse (e.g., topical use) in the treatment and/or prevention of actinickeratosis. In certain aspects, KX-01 is for use at the doses, dosingschedules, and/or one or more affected area in a subject in need thereofas described herein.

In one aspect, this application pertains at least in part, to use (e.g.,topical use) of KX-01 in the treatment and/or prevention of actinickeratosis. In certain aspects, KX-01 is used at the doses, dosingschedules, and/or one or more affected area in a subject in need thereofas described herein.

In one aspect, this application pertains at least in part, to use ofKX-01 in the manufacture of a medicament for the treatment and/orprevention of actinic keratosis. In certain aspects, KX-01 is used atthe doses, dosing schedules, and/or one or more affected area in asubject in need thereof as described herein.

Unless explicitly indicated otherwise, the terms “KX-01” and “KX2-391”refer to the basic form of the compound, i.e., the “free base,” whichhas the following structure:

The term “KX-01 MSA” refers to the mesylate salt of KX-01, i.e., thesalt compound resulting from reacting KX-01 with methane sulfonic acid.

“KX-01”, as used herein, may also be called “KX01”, “KX2-391”, or“KX-2-391”.

KX-01, and salts thereof, e.g., KX-01 MSA, and their preparation aredisclosed in PCT Application Publication Nos. WO 2008/082637, WO2008/144045, and WO 2010/135429. These publications are incorporated byreference herein in their entireties.

Actinic keratosis, i.e., “AK,” is a common precancerous skin conditioncaused by excessive exposure to ultraviolet light. AKs are rough, dry,tan-, pink-, or red-colored blemishes (lesions) that often appear on theparts of the head, including the face, throat, neck, nose, forehead,ears, or lips. AKs may also appear or other body parts that receiveprolonged, intense sunlight, e.g., the hands, the back, and other areason the trunk and legs.

As used herein, the term “trunk” refers to the portion of a subject thatis not an arm, a leg, or the head.

AKs are most common in fair-skinned, middle-aged or elderly individuals.A subject suffering from AKs may have a single lesion or multiplelesions. AK can lead to squamous cell carcinoma.

Clinical variants of AK include: classic (or common), hypertrophic (orhyperkeratotic), atrophic, AK with cutaneous horn, pigmented AK, actiniccheilitis, and Bowenoid AK. Unless explicitly indicated otherwise, themethods described herein are applicable to all clinical variants,including those listed herein.

Treatments for AK include cryosurgery, surgical excision and/or scrapingof the affected areas, photodynamic therapy, and topical formulations(e.g., creams, gels, patches, etc.) comprising a steroid, fluorouracil,diclofenac, imiquimod, 5-aminolaevulinic acid (Ameluz®).

The approved treatment for AK is Picato (Ingenol Mebutate)®, a gelcontaining ingenol mebutate (0.015% or 0.05%). The gel is applied to theaffected areas on the face or scalp once daily for three consecutivedays (0.015%), or on the trunk or extremities once daily for twoconsecutive days (0.05%).

The skin toxicity associated with the use of other AK treatments, suchas with Picato (Ingenol Mebutate)®, is known to produce unwanted sideeffect or adverse reactions, i.e., local skin reactions (LSRs), whichinclude vesiculation, postulation, erosion, ulceration, redness,swelling, flaking, scaling, hard lumps, dryness, pus, and blistering.Other side effects include application site pain, application sitepruritus, application site irritation, application site swelling,application site burning sensation, application site infection,periorbital edema, nasopharyngitis, chills, sore throat, drooping eyes,puffy eyes, hypopigmentation, hyperpigmentation, and headache.

The phrase “until the actinic keratosis clears,” as used herein, refersto the instance where the lesions on a subject suffering from AK havesubstantially or completely disappeared from the treated area on thesubject. In one embodiment, “substantially,” in this context, refersmore than 50% of the AK lesions have disappeared from the treated areaon the subject. In another embodiment, “substantially” refers more than60% of the AK lesions have disappeared from the treated area on thesubject. In another embodiment, “substantially” refers more than 70% ofthe AK lesions have disappeared from the treated area on the subject. Inanother embodiment, “substantially” refers more than 80% of the AKlesions have disappeared from the treated area on the subject. Inanother embodiment, “substantially” refers more than 90% of the AKlesions have disappeared from the treated area on the subject. Inanother embodiment, “substantially” refers more than 95% of the AKlesions have disappeared from the treated area on the subject. Inanother embodiment, “substantially” refers more than 99% of the AKlesions have disappeared from the treated area on the subject.

As used throughout the disclosure, the singular forms “a,” “and,” and“the” include plural referents unless the context clearly dictatesotherwise. Thus, for example, reference to “a method” includes aplurality of such methods and reference to “a dose” includes referenceto one or more doses and equivalents thereof known to those skilled inthe art, and so forth.

The term “comprising” is intended to mean that the method includes therecited elements, but do not exclude others. “Consisting essentially of”when used to define methods, shall mean excluding other elements of anyessential significance to the combination when used for the intendedpurpose. Thus, a method consisting essentially of the elements asdefined herein would not exclude substantial method steps. “Consistingof” shall mean excluding more than substantial method steps. Embodimentsdefined by each of these transition terms are within the scope of thisapplication.

Unless explicitly indicated otherwise, the terms “approximately” and“about” are synonymous. In one embodiment, “approximately” and “about”refer to the recited amount, value, or duration ±5%, ±4.5%, ±4%, ±3.5%,±3%, ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%,±0.5% ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.09%, ±0.08%, ±0.07%, ±0.06%,±0.05%, ±0.04%, ±0.03%, ±0.02%, or ±0.01%. In another embodiment,“approximately” and “about” refer to the listed amount, value, orduration ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1%, ±0.9%, ±0.8%, ±0.7%,±0.6%, ±0.5%. In yet another embodiment, “approximately” and “about”refer to the listed amount, value, or duration ±1%. In yet anotherembodiment, “approximately” and “about” refer to the listed amount,value, or duration ±0.5%. In yet another embodiment, “approximately” and“about” refer to the listed amount, value, or duration ±0.1%.

The term “subject” includes any living organism that has actinickeratosis, or is at a risk of developing actinic keratosis. In oneembodiment, the term “subject” refers to a mammal that has actinickeratosis, or is at a risk of developing actinic keratosis. In oneembodiment, the term subject refers to a human being that has actinickeratosis, or is at a risk of developing actinic keratosis. The term“patient” is meant to be synonymous with “subject,” unless explicitlyindicated otherwise.

The term “therapeutically effective amount”, as used herein, refers toan amount of a pharmaceutical agent, e.g., KX-01, to treat, ameliorate,or prevent an identified disease or condition, e.g., AK, or to exhibit adetectable therapeutic or inhibitory effect. The effect can be detectedby any assay method known in the art. The precise effective amount for asubject will depend upon the subject's body weight, size, and health;the nature and extent of the condition; and the therapeutic orcombination of therapeutics selected for administration. Therapeuticallyeffective amounts for a given situation can be determined by routineexperimentation that is within the skill and judgment of the clinician.

For any compound, the therapeutically effective amount can be estimatedin animal models, usually rats, mice, rabbits, dogs, or pigs. The animalmodel may also be used to determine the appropriate concentration rangeand route of administration. Such information can then be used todetermine useful doses and routes for administration in humans.Therapeutic/prophylactic efficacy and toxicity may be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., ED₅₀ (the dose therapeutically effective in 50% of thepopulation) and LD₅₀ (the dose lethal to 50% of the population). Thedose ratio between toxic and therapeutic effects is the therapeuticindex, and it can be expressed as the ratio, LD₅₀/ED₅₀. The dosage mayvary within this range depending upon the dosage form employed andsensitivity of the subject.

Dosage and administration are adjusted to provide sufficient levels ofthe active ingredient or to maintain the desired effect. Factors whichmay be taken into account include the severity of the disease state,location of the disease on the subject, general health of the subject,age, weight, and gender of the subject, diet, time and frequency ofadministration, drug combination(s), reaction sensitivities, andtolerance/response to therapy. KX-01 may be administered every day,every other day, every three days, every four days, every five days,every six days, every week, biweekly, or once every two weeks dependingon half-life and clearance rate.

For any of the methods described herein, KX-01 may be administeredtopically, intradermally, interepidermally, intragingivally,intraocularly, nasally, ophthalmically, percutaneously, periodontally,subconjuctivally, sublingually, transmucosally, or otically. In oneembodiment, KX-01 may be administered topically.

All percentages and ratios used herein, unless otherwise indicated, areby weight.

Every document cited herein, including any cross referenced or relatedpatent or application, is hereby incorporated herein by reference in itsentirety unless expressly excluded or otherwise limited. The citation ofany document is not an admission that it is prior art with respect toany subject matter disclosed or claimed herein or that it alone, or inany combination with any other reference or references, teaches,suggests or discloses any such subject matter. Further, to the extentthat any meaning or definition of a term in this document conflicts withany meaning or definition of the same term in a document incorporated byreference, the meaning or definition assigned to that term in thisdocument shall govern.

While particular embodiments of the disclosure have been illustrated anddescribed, various other changes and modifications can be made withoutdeparting from the spirit and scope of the disclosure. The scope of theappended claims includes all such changes and modifications that arewithin the scope of this disclosure.

Other features and advantages of the present application are apparentfrom the different examples. The provided examples illustrate differentcomponents and methodology useful in practicing the present application.

The examples do not limit the claimed application. Based on the presentdisclosure the skilled artisan can identify and employ other componentsand methodology useful for practicing the present applications.

EXAMPLES

Two clinical studies (detailed in Examples 1 and 2) were conducted toevaluate the activity and safety of KX-01 administered topically insubjects with actinic keratosis. Preliminary data from these studiessuggested that KX-01 demonstrates clinically relevant activity in thetreatment of actinic keratosis of the face and scalp, and of theforearm. KX-01, when administered for 5 days, has a very good safetyprofile with limited systemic exposure. Local tolerability appears to bevery good with local skin reactions (LSRs) that consist primarily ofmild to moderate erythema and scaling. KX-01 was found to be safe.

Example 1—A Phase 1 Study of KX-01 Administered Topically for 3 or 5Days to the Forearm

A Phase 1, single-center, safety, tolerability and pharmacokinetic studyof KX-01 was performed on subjects with AK on the dorsal forearm. Thiswas an open-label, uncontrolled, nonrandomized, sequential groupclinical trial conducted at a single investigational center in theUnited States. The primary objectives of the study were to assess thesafety, tolerability and pharmacokinetics of KX-01 in subjects with AK.The secondary objective was to evaluate the activity of KX-01administered topically to the dorsal forearm in subjects with AK.

Adult subjects of 18 years of age and older with clinically typical AKlesions in the dorsal forearm who met all inclusion criteria and did notmeet an exclusion criterion were enrolled into sequential cohorts.

-   -   Cohort 1, N=4, 0.5 mg KX-01 topically administered to a 25 cm²        area with 4-8 clinically typical AK lesions on the dorsal        forearm, daily for 3 consecutive days.    -   Cohort 2, N=10, 2.0 mg KX-01 topically administered to a 100 cm²        area with 8-16 clinically typical AK lesions on the dorsal        forearm, daily for 3 consecutive days.    -   Cohort 3, N=8, 0.5 mg KX-01 topically administered to a 25 cm²        area with 4-8 clinically typical AK lesions area of the dorsal        forearm, daily for 5 consecutive days.    -   Cohort 4, N=8, 2.0 mg KX-01 topically administered to a 100 cm²        area with 8-16 clinically typical AK lesions of the dorsal        forearm, daily for 5 consecutive days.

KX-01 was administered topically on treatment days. All subjects weremonitored for safety and tolerability that included LSRs, AEs, vitalsigns, clinical laboratory tests, ECGs, and physical examinations atbaseline and at pre-defined time points during treatment and follow-upon days 1, 2, 3, 4, 5, 8, 10, 17, 31 and 45. AK lesion counts wererecorded at baseline on days 4, 10, 17, 31, and 45. Standardizedphotography of the treatment area was performed. Plasma samples forpharmacokinetics were collected at preplanned time points on Days 1-8.

LSRs (erythema, flaking/scaling, crusting, swelling,vesiculation/pustulation, erosion/ulceration) were assessed by theinvestigator or trained designee using a 4-point scale according to theprotocol. The subject's assessment of the symptoms (stinging/burning,pruritus) associated with irritation of the treatment area was evaluatedon a 4-point scale (0=none, 1=mild, 2=moderate, 3=severe). Subjects werequeried for spontaneously reported AEs at each study visit beforeassessment of LSRs. LSRs and AEs were reported separately. All LSRs wereto be followed to resolution or stabilization.

A total of 30 subjects were enrolled and 29 subjects completed thestudy. The subject population consisted of 19 male and 11 femalesubjects. Overall mean age was 63.1 years and mean weight was 194.9pounds. All except one subject were white. All were of non-Hispanic orLatino ethnicity. Demographics and baseline characteristics by cohortare summarized in Table 1.

TABLE 1 Demographics and Baseline Characteristics of Subjects Cohort 1Cohort 2 Cohort 3 Cohort 4 Demographics and (N = 4) 0.5 mg (N = 10) 2 mg(N = 8) 0.5 mg (N = 8) 2 mg Baseline KX-01/25 cm² KX-01/100 cm² KX-01/25cm² KX-01/100 cm² Characteristics QD x 3 days QD x 3 days QD x 5 days QDx 5 days Mean Age(years) 63.0 61.8 63.0 64.9 Gender (M/F) 3/1 6/4 5/35/3 Race White 4 9 8 8 Other 0 1 0 0 Mean Weight (lbs) 200.8 180.2 215.0190.3 Number of Baseline AK 5.0 (4-5) 11.5 (8-16) 6.0 (5-6) 11.0 (10-16)Lesions - Median (Range) M = male; F = female

Local tolerability was acceptable. All 30 subjects had LSRs as assessedby the Investigator. In general, LSRs appeared on day 2, tended to peakaround day 5 for the 3-day treatment cohorts (Cohorts 1 and 2) andaround day 10 for the 5-day treatment cohorts (Cohorts 3 and 4), beforereturning to or close to baseline. No subject had an LSR score of 4 inany category. No subject had a vesicle or pustule. Fifteen subjects haderythema and/or flaking/scaling with a score 1 or 2 at day 45 that werefollowed until resolution or stabilization. Maximum LSRs are displayedby category and cohort in Table 2.

Subjects were specifically inquired about stinging, burning and pruritusat the application site at every visit. The maximum scores for eachsymptom are summarized in Table 2. In general, symptoms arose as earlyas day 2, peaked in severity and incidence at day 8-day 10, and resolvedby day 45. Two subjects (one in Cohort 2 and one in Cohort 4) who hadmild to moderate symptoms are being followed to resolution orstabilization. There was one subject in Cohort 3 who had severe prurituson Day 17 that reduced to mild severity at the next visit on Day 31without requiring concomitant medication.

TABLE 2 Number of Subjects (%) with Maximum LSR Score by LSR Categoryand by Cohort LSRs Cohort 1 (N = 4) Cohort 2 (N = 10) Cohort 3 (N = 8)Cohort 4 (N = 8) 0.5 mg KX-01 2 mg KX-01 0.5 mg KX-01 2 mg KX-01 25 cm²QD × 3 days 100 cm² QD × 3 days 25 cm² QD × 5 days 100 cm² QD × 5 daysMax score 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 Max LSR Score asAssessed by Investigator Erythema 0 2 1 1 0 0 6 2 2 0 0 2 4 2 0 0 2 4 20 (50%) (25%) (25%) (60%) (20%) (20%) (25%) (50%) (25%) (25%) (50%)(25%) Flaking/ 0 3 0 1 0 1 2 1 6 0 0 2 2 4 0 0 2 4 2 0 scaling (75%)(25%) (10%) (20%) (10%) (60%) (25%) (25%) (50%) (25%) (50%) (25%)Crusting 4 0 0 0 0 5 5 0 0 0 1 7 0 0 0 4 4 0 0 0 (100%) (50%) (50%)(13%) (88%) (50%) (50%) Swelling 4 0 0 0 0 8 2 0 0 0 4 1 0 3 1 6 1 0 0(100%) (80%) (20%) (50%) (13%) (38%) 0 (13%) (75%) (13%) Vesicles/ 4 0 00 0 10 0 0 0 0 8 0 0 0 0 8 0 0 0 0 pustules (100%) (100%) (100%) (100%)Erosions/ 4 0 0 0 0 10 0 0 0 0 8 0 0 0 0 7 1 0 0 0 ulcers (100%) (100%)(100%) (88%) (13%) Max LSR Score as Assessed by Subjects Stinging 3 1 00 8 2 0 0 6 1 1 0 5 3 0 0 (75%) (25%) (80%) (20%) (75%) (13%) (13%)(63%) (38%) Burning 4 0 0 0 6 3 1 0 4 3 1 0 4 4 0 0 (100%) (60%) (30%)(10%) (50%) (38%) (13%) (50%) (50%) Pruritus 3 1 0 0 4 6 0 0 2 4 1 1 0 44 0 (75%) (25%) (40%) (60%) (25%) (50%) (13%) (13%) (50%) (50%) LSR =local skin reaction; Max = maximum. Investigator's Assessment of LSR,5-point scale LSR score: 0 = none, 1 = minimal, 2 = mild, 3 = moderate,4 = severe. Subject's Assessment of LSR, 4-point scale LSR score: 0 =none, 1 = mild, 2 = moderate, 3 = severe.

As a post-hoc analysis of LSRs, a composite score was calculated byadding the scores of the 6 LSR categories for each subject as determinedby the investigator at each assessment visit. The range of the possiblecomposite scores is 0-24. FIG. 1 displays the mean composite scores overtime by cohort.

Four of 30 subjects reported 10 treatment emergent adverse events(TEAEs). All TEAEs were mild to moderate, and responded to treatmentwhen given. No TEAE was reported for Cohort 1. One subject in Cohort 2had mild upper respiratory tract infection on days 38-44, that was notrelated to study drug. One subject in Cohort 3 had headache on day 2,back pain on Days 4-5, and urinary tract infection on days 6-14; theseAEs were of mild severity and were considered possibly related to studydrug. The same subject had mild arthralgia on days 16-49, moderateosteoarthritis on day 16-49, and moderate pain from injection ofplatelet-rich plasma for treatment of osteoarthritis on day 43-44 thatwas considered not related to study drug. In Cohort 4, one subject hadbasal cell carcinoma, not in the treatment area, of moderate severity ondays 3-25 that was considered not related to study drug; this wasremoved surgically. Another subject reported moderate muscular weaknessand myositis that were unrelated to study drug, but related tofenofibrate that was being taken for hyperlipidemia. Fenofibrate wasdiscontinued. On follow-up, muscular weakness resolved and myositisimproved but was still ongoing.

There was no serious adverse event (SAE) or death in the study. No onediscontinued treatment or follow-up for adverse events. One subject inCohort 2 withdrew consent for personal reasons after 1 day of study drugapplication.

Clinical Activity:

All 4 cohorts showed reductions in mean baseline AK lesion counts overtime and some patients demonstrated complete clearance at day 45 (Table3).

TABLE 3 Complete/Partial Clearance by Cohort and Summary of Median(Range) of AK Lesion Counts by Visit and Cohort, in KX01-AK-01-US Cohort1 Cohort 2 Cohort 3 Cohort 4 (N = 4) 0.5 mg (N = 10) 2 mg (N = 8) 0.5 mg(N = 8) 2 mg KX-01 25 cm² KX-01 100 cm² KX-01 25 cm² KX-01 100 cm²Activity QD x 3 days QD x 3 days QD x 5 days QD x 5 days CompleteClearance 1/4 (25%) 0/10 4/8 (50%) 1/8 (13%) on Day 45^(a) PartialClearance on 2/4 (50%) 3/10 (30%) 5/8 (63%) 4/8 (50%) Day 45^(b) Summaryof Median (Min, Max) of AK Lesion Counts by Visit by Cohort Day 1(Baseline) 5.0 (4, 5) 11.5 (8, 16) 6.0 (5, 6) 11.0 (10, 16) Day 4 5.0(4, 5) 9.0 (6, 16) Not done Not done Day 10 5.0 (4, 5) 7.0 (6, 11) 5.0(5, 6) 10.0 (10, 10) Day 17 4.5 (3, 5) 7.0 (5, 15) 5.0 (4, 6) 10.0 (10,11) Day 31 3.5 (1, 5) 7.0 (1, 15) 1.0 (0, 6) 6.0 (0, 11) Day 45 2.5 (0,4) 4.0 (1, 10) 0.5 (0, 4) 4.5 (0, 12) ^(a)Complete Clearance - 100%reduction in AK lesions on Day 45 compared to Baseline. ^(b)PartialClearance - ≥75% reduction in AK lesions on Day 45 compared to Baseline.

This study provided preliminary evidence of clinical activity oftopically administered KX-01 for AK treatment. The data also suggestedthat the 5-day regimen may provide better activity than the 3-dayregimen as shown by higher rates of complete and partial clearance of AKfor the subjects treated for 5 days. Local skin reactions appeared to beprimarily mild in nature. The safety and activity findings from thisstudy provided the impetus to proceed with a larger multicenter study.

Example 2a—A Phase 2a Study of KX-01 Administered Topically to the Faceor Scalp

An ongoing Phase 2a, open-label, multicenter, activity and safety studyof KX-01 administered topically in subjects with AK on the face or scalpis described herein. The primary objective is to evaluate the activityof KX-01 administered topically to the face or scalp in subjects with AKby determining complete response rate, defined as 100% clearance on Day57. Secondary objectives are to assess the activity of KX-01administered topically during Days 1-57 based on reduction of AK lesioncounts from baseline, assess the safety and tolerability andpharmacokinetics, and contrast the dose regimens (5-day treatment with3-day treatment) in terms of activity and safety in subjects with AK onthe face or scalp. This uncontrolled, nonrandomized trial is beingconducted at 16 investigational sites in the United States. Enrollmentis sequential for 2 cohorts of approximately 80 subjects each.Enrollment is closed for Cohort 1 and ongoing for Cohort 2. The twotreatment cohorts are summarized below:

-   -   Cohort 1: 0.5 mg KX-01 administered topically to a contiguous        treatment area of 25 cm² with 4-8 clinically typical AK lesions        for 5 consecutive days    -   Cohort 2: 0.5 mg KX-01 administered topically to a contiguous        treatment area of 25 cm² with 4-8 clinically typical AK lesions        for 3 consecutive days

0.5 mg KX-01 is administered topically to an area of 25 cm² on the faceor scalp by site staff on treatment days. All subjects are monitored forsafety and tolerability that included LSRs, hyperpigmentation,hypopigmentation, scarring, AEs, vital signs, clinical laboratory tests,ECGs, and physical examinations at baseline at predefined time pointsduring treatment and follow-up on days 1, 2, 3, 4, 5, 8, 15, 29, and 57.AK lesion counts are recorded at baseline, days 8, 15, 29, and 57. Thosewho achieve complete clearance of AK on day 57 will be followed for AKlesion counts, LSRs and AEs at 3, 6, 9, and 12 months after day 57during the recurrence follow-up period. Standardized photography oftreatment area is performed at baseline, day 8 and day 57. Plasmasamples are being collected at preplanned time points on days 1 and 5for Cohort 1, and on days 1 and 3 for Cohort 2.

LSRs (erythema, flaking/scaling, crusting, swelling,vesiculation/pustulation, erosion/ulceration) are assessed by theInvestigator or trained designee using a grading scale from 0 (notpresent) to 4 (worst) based on protocol-defined LSR grading criteria.Absence or presence of hyperpigmentation, hypopigmentation and scarringare also assessed. Application site reactions not classified as LSRs arereported as AEs. Subjects are queried for spontaneously reported AEs ateach study visit before assessment of LSRs. LSRs and AEs are reportedseparately. All LSRs, pigmentation, and scarring in the treatment areawill be followed to resolution or stabilization.

82 eligible subjects were enrolled in Cohort 1. Demographics andbaseline characteristics of subjects are displayed in Table 4. There hasbeen no discontinuation prior to day 57. As this study is ongoing, thedata presented are to be considered preliminary. Data from Cohort 2(3-day dosing) are not yet available.

TABLE 4 Demographics and Baseline Characteristics of Subjects in Cohort1 Demographics and Baseline Cohort 1 (N = 82) 0.5 mg CharacteristicsKX-01, 25 cm² QD x 5 days Mean Age (years) 69.0 Gender: Male/Female 74/8Race - White 82   Ethnicity - Hispanic or Latino/  2/80 Non-Hispanic orLatino Skin Type I/II/III/IV/V/VI 11/37/26/7/1/0 AK lesion count atBaseline - 6.0 (4, 8) Median (Min, Max) Mean Weight (pounds) 194.07

Of the 67 subjects who had day 57 visits, 7 had no LSR in the treatmentarea throughout the study. The majority of subjects were found to haveerythema (60/67, 90%) and flaking/scaling (47/67, 70%). Most of theseLSRs were scored at 1 and 2. Crusting was observed in 26/67 (39%) ofsubjects and was mostly scored at 1. Swelling was reported in 14/67(21%) subjects. All swellings were scored at 1 except for two subjects,one scored at 2, and another scored at 3. Three subjects hadvesiculation/pustulation and 9 subjects had erosion/ulceration. LSRswere generally observable from day 3 and reached a maximum score by day5 and day 8 before decreasing to or close to baseline by day 29 and 57.Of the 60 subjects who had LSRs, all but 8 subjects had LSRs return tobaseline at day 57. These 8 subjects had erythema of score 1 or 2,flaking/scaling, and/or crusting of score 1, and were being followeduntil resolution or stabilization by the investigators.

A detailed summary of local skin reactions (LSRs) from this studyKX01-AK-002 is provided below in Table 5.

TABLE 5 Summary of Local Skin Reactions by Visit Evaluable Set in Cohort1 Flaking/ Vesiculation/ Erosion/ Visit Grade Erythema Scaling CrustingSwelling Pustulation Ulceration Day 1, n (%) 0 56/67 (84) 55/67 (82)62/67 (93) 67/67 (100) 67/67 (100) 67/67 (100) 1 11/67 (16) 12/67 (18)5/67 (7) 0 0 0 2 0 0 0 0 0 0 3 0 0 0 0 0 0 4 0 0 0 0 0 0 Day 2, n (%) 044/67 (66) 51/67 (76) 64/67 (96) 67/67 (100) 67/67 (100) 67/67 (100) 120/67 (30) 15/67 (22) 2/67 (3) 0 0 0 2 3/67 (4) 1/67 (1) 1/67 (1) 0 0 03 0 0 0 0 0 0 4 0 0 0 0 0 0 Day 3, n (%) 0 32/67 (48) 46/67 (69) 63/67(94) 67/67 (100) 67/67 (100) 66/67 (99)  1 24/67 (36) 14/67 (21) 3/67(4) 0 0 1/67 (1)  2 10/67 (15) 5/67 (7) 1/67 (1) 0 0 0 3 1/67 (1) 2/67(3) 0 0 0 0 4 0 0 0 0 0 0 Day 4, n (%) 0 19/67 (28) 43/67 (64) 61/67(91) 65/67 (97)  66/67 (99)  65/67 (97)  1 26/67 (39) 16/67 (24) 4/67(6) 2/67 (3)  1/67 (1)  2/67 (3)  2 17/67 (25) 5/67 (7) 2/67 (3) 0 0 0 35/67 (7) 3/67 (4) 0 0 0 0 4 0 0 0 0 0 0 Day 5, n (%) 0 12/67 (18) 35/67(52) 56/67 (84) 58/67 (87)  65/67 (97)  61/67 (91)  1 19/67 (28) 21/67(31)  9/67 (13) 7/67 (10) 2/67 (3)  6/67 (9)  2 27/67 (40)  9/67 (13)2/67 (3) 1/67 (1)  0 0 3  9/67 (13) 2/67 (3) 0 1/67 (1)  0 0 4 0 0 0 0 00 Day 8, n (%) 0 14/67 (21) 26/67 (39) 51/67 (76) 64/67 (96)  67/67(100) 65/67 (97)  1 24/67 (36) 18/67 (27) 15/67 (22) 3/67 (4)  0 1/67(1)  2 25/67 (37) 15/67 (22) 1/67 (1) 0 0 1/67 (1)  3 4/67 (6)  8/67(12) 0 0 0 0 4 0 0 0 0 0 0 Day 15, n (%) 0 27/67 (40) 39/67 (58) 63/67(94) 67/67 (100) 67/67 (100) 66/67 (99)  1 25/67 (37) 14/67 (21) 4/67(6) 0 0 1/67 (1)  2 13/67 (19)  9/67 (13) 0 0 0 0 3 2/67 (3) 5/67 (7) 00 0 0 4 0 0 0 0 0 0 Day 29, n (%) 0 45/67 (67) 51/67 (76) 65/67 (97)66/67 (99)  67/67 (100) 67/67 (100) 1 18/67 (27) 13/67 (19) 2/67 (3)1/67 (1)  0 0 2 4/67 (6) 2/67 (3) 0 0 0 0 3 0 1/67 (1) 0 0 0 0 4 0 0 0 00 0 Day 57, n(%) 0 53/67 (79) 57/67 (85) 63/67 (94) 67/67 (100) 67/67(100) 67/67 (100) 1 12/67 (18) 10/67 (15) 4/67 (6) 0 0 0 2 2/67 (3) 0 00 0 0 3 0 0 0 0 0 0 4 0 0 0 0 0 0 Note 1: Cohort 1 = 25 cm{circumflexover ( )}2 treatment area/5 consecutive treatment days/0.5 mg KX-01administered topically. 2: Data are presented as number of subjects witha specific finding/number of subjects assessed at each visit. Percentagecalculated is indicated in parenthesis.

Table 6 presents the maximum post-dose LSR score and the maximal LSRscores experienced in the combined Picato (Ingenol Mebutate)® Phase 3registration trials for the treatment of AK of the face and scalp. Thedata suggest that 5-day treatment with KX-01 administered topically mayhave a more benign local safety profile compared to that reported forPicato (Ingenol Mebutate).

TABLE 6 Side-by-Side Summary of Maximal Local Skin Reactions Post-Baseline for Picato (Ingenol Mebutate) ® Pep005 Gel Local Skin0.015%^(a) KX-01^(b) Responses Grade N = 274 N = 67 Erythema 0 1 (<1%) 7(10%) 1 25 (9%) 16 (24%) 2 56 (20%) 32 (48%) 3 125 (46%) 12 (18%) 4 66(24%) 0 (0%) Flaking/Scaling 0 7 (3%) 20 (30%) 1 52 (19%) 14 (21%) 2 91(33%) 20 (30%) 3 98 (36%) 13 (19%) 4 25 (9%) 0 (0%) Crusting 0 44 (16%)41 (61%) 1 85 (31%) 20 (30%) 2 64 (23%) 6 (9%) 3 64 (23%) 0 (0%) 4 16(6%) 0 (0%) Swelling 0 56 (20%) 53 (79%) 1 88 (32%) 12 (18%) 2 67 (25%)1 (1%) 3 48 (18%) 1 (1%) 4 14 (5%) 0 (0%) Vesiculation/ 0 119 (43%) 64(96%) Pustulation 1 36 (13%) 3 (4%) 2 53 (19%) 0 (0%) 3 50 (18%) 0 (0%)4 15 (6%) 0 (0%) Erosion/ 0 186 (68%) 57 (85%) Ulceration 1 55 (20%) 9(13%) 2 26 (10%) 1 (1%) 3 5 (2%) 0 (0%) 4 1 (<1%) 0 (0%) ^(a)Source: NDA202833; Statistical Review and Evaluation Pep005 (Ingenol Mebutate) gel,0.015%; Table 9. ^(b)Values are number of subjects in the Evaluable Set,categorized per their maximal post-baseline LSR grade. Percentages arebased on the number of subjects.

As a post-hoc analysis of LSRs, a composite score was calculated byadding the scores of the 6 LSR categories for each subject at eachassessment visit. The range of possible composite scores is 0-24. FIG. 2displays the mean composite scores over time in Cohort 1.

All 82 subjects entered into Cohort 1 were included in the AE analysis.Twenty-six of 82 subjects in Cohort 1 reported a total of 54 TEAEs. AllTEAEs were mild to moderate except for one severe case of small bowelobstruction that was reported as an SAE (discussed below). Sevensubjects reported 12 TEAEs that were considered related to KX-01. Therewere 6 cases of application site reaction which included 1 mildtenderness, 2 mild stinging, and 3 mild pruritus. Othertreatment-related AEs were 2 cases of mild dizziness, 1 mild darkeningof hair color near the treatment area and 1 mild headache. There was acase of “worsening of elevated alanine transaminase” from a baseline of58 IU/mL to 61 IU/mL on day 22. A case of mild conjunctivitis near thetreatment area was reported on day 4 and lasted until day 5. The subjectclarified that there was only mucus secretion from the eye due to use ofcontact lens. There was no associated redness, itch, pain or swelling,and KX-01 did not get into the eye.

There were 3 SAEs that occurred in 2 subjects, none of which wereconsidered related to study drug. All SAEs required hospitalization. Onesubject was an 84-year old male subject who had small bowel obstructionon day 56, transurethral resection of prostate (TURP) for benignprostatic hypertrophy (BPH) on day 67, and postoperative cardiacischemia on day 72. He recovered thereafter. Another subject was a67-year old white male who was hospitalized for TURP for BPH on day 17.He recovered uneventfully.

There was one case of cancer that was unrelated to study drug—a 61-yearold man who was diagnosed to have squamous cell carcinoma not in thetreatment area on day 3 that was subsequently excised. This AE was notconsidered serious.

Among the enrolled subjects, 67 have reached the day 57 visit.Twenty-four of 67 subjects (36%, 95% CI (confidence interval): 24%-47%)achieved the primary endpoint defined as 100% clearance of AK lesions inthe treatment area on day 57. Of the 35 subjects who received treatmenton their faces, 15 (43%, 95% CI: 26%-59%) achieved 100% clearance, while9 of 32 subjects (28%, 95% CI: 13%-44%) who received treatment on theirscalp achieved 100% clearance.

Thirty-four of 67 subjects (51%, 95% CI: 39%-63%) had at least 75%reduction of AK lesions on day 57 compared to baseline; 21/35 (60%, 95%CI: 44%-76%) who had treatment on the face and 13/32 (41%, 95% CI:24%-58%) who had treatment on the scalp. These data are summarized inTable 7.

TABLE 7 Analysis of Clearance Rate at Day 57—Evaluable Set in Cohort 1Number of Total Wald Wald Subjects Number 95% 95% with of Lower UpperTreat- Specified Subjects Con- Con- Clearance ment Clearance at Binomialfidence fidence (a) Area at Day 57 Day 57 Proportion Limit Limit    100%Face 15 35 0.43 0.26 0.59 Scalp  9 32 0.28 0.13 0.44 Overall 24 67 0.360.24 0.47 >=75% Face 21 35 0.60 0.44 0.76 Scalp 13 32 0.41 0.24 0.58Overall 34 67 0.51 0.39 0.63 Note 1: Data cutoff date is 12 Oct. 2016.2: Cohort 1 = 25 cm{circumflex over ( )}2 treatment area/5 consecutivetreatment days/0.5 mg KX-01 administered topically. (a) Clearance iscalculated relative to assessment at Day 1 visit.

Activity of KX-01 in terms of reduction of AK lesion counts issummarized in Table 8. Over the 57-day observation period, there was aprogressive decline in median lesion count, from 6.0 to 2.0.

TABLE 8 Summary of AK Lesion Counts by Visit in Cohort 1, KX01-AK-002 AKLesion Counts Day 1 Day 8 Day 15 Day 29 Day 57 N 67 60^(a) 63^(a) 67 67Median 6.0   5.0   4.0 2.0 2.0 Min, Max 4, 8 0, 10 0, 9 0, 8 0, 9

KX-01 administered topically once daily for 5 days appears to be safeand well tolerated. There were few treatment-related adverse events andno treatment-related severe or serious adverse events.

The 5-day dosing regimen of KX-01 was associated with mild andreversible LSRs consisting primarily of erythema and flaking/scaling. Inthis study, no Grade 4 LSRs were observed after 5 days of treatment withKX-01.

Preliminary results (Example 1, Example 2a, and Example 2b) indicatethat KX-01 administered topically once daily for up to 5 daysdemonstrates clinically relevant activity in the treatment of AK of thedorsal forearm, as well as both the face and scalp. The data suggestthat the 5-day regimen of KX-01 has greater activity than the 3-dayregimen.

Cross-study tabulation of results with those published for Picato(Ingenol Mebutate)® suggests that the activity of the 5-day treatmentregimen of KX-01 administered topically may be comparable to thatobserved in the Picato (Ingenol Mebutate)® Phase 3 studies (Table 9).

TABLE 9 Cross-Study Tabulation of Complete Clearance Rates - KX-01 andPicato (Ingenol Mebutate) ® KX-01 KX-01 Anatomical 3-day Topical 5-dayTopical Location Regimen^(a) Regimen^(a) Picato Gel^(b) Picato Gel^(b)Arm 1/4 (25%) 4/8 (50%) Study 3 Study 4 (25 cm² area)  22/84 (26%) 27/59 (46%) Face TBD 15/35 (43%) Study 1 Study 2 46/109 (42%) 58/111(52%) Scalp TBD 9/32 (28%) Study 1 Study 2  4/26 (15%)  9/31 (29%)^(a)Studies KX01-AK-01-US and KX01-AK-002, data cut-off date is 12 Oct.2016. ^(b)Picato (Ingenol Mebutate) ® Prescribing Information, September2016.

Pharmacokinetic results following up to 5 consecutive days of treatmentwith KX-01 showed low systemic exposure (<1 ng/mL) and limited drugaccumulation in the majority of subjects. The data suggest that 5 daysof topical treatment with KX-01 has optimal activity and safety.

Example 2b—A Phase 2a Study of KX-01 Administered Topically to the Faceor Scalp

The Phase 2a trial described in Example 2a was completed with 84eligible subjects enrolled in each of two cohorts: one cohort wassubjected to the treatment for 5 consecutive days, and the other cohortwas subjected to the treatment for 3 consecutive days. The results aredescribed below and in FIG. 5.

TABLE 10 AK Clearance in the Two Cohort at Day 57 After TreatmentClearance of AK Responders/Total Number (%) Cohort at day 57 Face ScalpOverall 5-day  100% 23/44 (52%) 13/40 (33%) 36/84 (43%) ≥75% 29/44 (66%)18/40 (45%) 47/84 (56%) 3-day  100% 20/66 (30%) 7/18 (39%) 27/84 (32%)≥75% 35/66 (53%) 9/18 (50%) 44/84 (52%)

TABLE 11 Side-by-Side Summary of Maximal Local Skin Reactions Post-Baseline for Picato (Ingenol Mebutate) ® Pep005 Gel KX-01^(b) KX-01^(b)Local Skin 0.015%^(a) (5-day) (3-day) Responses Grade N = 274 N = 84 N =84 Erythema 0 1 (<1%) 15 (18%) 30 (36%) 1 25 (9%) 16 (19%) 22 (26%) 2 56(20%) 35 (42%) 26 (31%) 3 125 (46%) 17 (20%) 6 (7%) 4 66 (24%) 1 (1%) 0(0%) Flaking/Scaling 0 7 (3%) 33 (39%) 39 (46%) 1 52 (19%) 10 (12%) 18(21%) 2 91 (33%) 24 (29%) 19 (23%) 3 98 (36%) 16 (19%) 8 (10%) 4 25 (9%)1 (1%) 0 (0%) Crusting 0 44 (16%) 51 (61%) 58 (69%) 1 85 (31%) 25 (30%)16 (19%) 2 64 (23%) 8 (10%) 9 (11%) 3 64 (23%) 0 (0%) 1 (1%) 4 16 (6%) 0(0%) 0 (0%) Swelling 0 56 (20%) 66 (79%) 76 (90%) 1 88 (32%) 16 (19%) 8(10%) 2 67 (25%) 1 (1%) 0 (0%) 3 48 (18%) 1 (1%) 0 (0%) 4 14 (5%) 0 (0%)0 (0%) Vesiculation/ 0 119 (43%) 80 (95%) 83 (99%) Pustulation 1 36(13%) 4 (5%) 0 (0%) 2 53 (19%) 0 (0%) 1 (1%) 3 50 (18%) 0 (0%) 0 (0%) 415 (6%) 0 (0%) 0 (0%) Erosion/ 0 186 (68%) 71 (85%) 79 (94%) Ulceration1 55 (20%) 12 (14%) 5 (6%) 2 26 (10%) 1 (1%) 0 (0%) 3 5 (2%) 0 (0%) 0(0%) 4 1 (<1%) 0 (0%) 0 (0%) ^(a)Source: NDA 202833; Statistical Reviewand Evaluation Pep005 (Ingenol Mebutate) gel, 0.015%; Table 9.^(b)Values are number of subjects in the Evaluable Set, categorized pertheir maximal post-baseline LSR grade. Percentages are based on thenumber of subjects.

Example 3—Summary of PK Results from Studies in Examples 1 and 2

KX-01 was tested in adult subjects with actinic keratosis of the dorsalforearm (Example 1) and actinic keratosis on the face or scalp (Examples2a and 2b). In Example 1, the plasma pharmacokinetics (PK) of KX-01following topical administration was evaluated by collection of plasmaon days 1 and 3 of the 3-day regimens and on days 1 and 5 of the 5-dayregimens (Table 12). In Examples 2a and 2b, plasma samples werecollected on days 1 and 5 of Cohort 1 (Table 13). Plasma samples atsimilar time points were collected on days 1 and 3 of Cohort 2. KX-01was measured in human plasma using a validated LC-MS/MS assay with alower limit of quantification (LLOQ) of 0.1 ng/mL.

TABLE 12 Example 1 - Treatment Regimens and PK Collection Times CohortAmount of KX-01 Dosing Regimen PK Collection Times (hr) 1 0.5 mg over 25cm² Once daily for Day 1: predose, 0.5, 1, 2, 4, 6, 8 and 3 days 12postdose Day 2: predose (24 postdose Day 1) Day 3: pre-dose, 0.5, 1, 2,4, 6, 8, 24, 48 and 120 postdose 2 2 mg over 100 cm² Once daily for Day1: predose, 0.5, 1, 2, 4, 6, 8, 12 3 days postdose Day 2: predose (24hours postdose Day 1) Day 3: pre-dose, 0.5, 1, 2, 4, 6, 8, 24, 48 and120 postdose 3 0.5 mg over25 cm² Once daily for Day 1: predose, 0.5, 1,2, 4, 6 postdose 5 days Day 2: predose (24 hours postdose Day 1) Day 5:predose, 0.5, 1, 2, 4, 6 and 72 postdose 4 2 mg over 100 cm² Once dailyfor Day 1: predose, 0.5, 1, 2, 4, 6 postdose 5 days Day 2: predose (24hours postdose Day 1) Day 5: predose, 0.5, 1, 2, 4, 6 and 72 postdose

TABLE 13 Examples 2a and 2b - Treatment Regimens and PK Collection TimesCohort Amount of KX-01 Dosing Regimen PK Collection Times (hr) 1 0.5 mgover 25 cm² Once daily for Day 1: pre-dose, 0.5, 1 and 4 postdose 5 daysDay 5: pre-dose, 0.5, 1 and 4 postdose 2 0.5 mg over 25 cm² Once dailyfor Day 1: pre-dose, 0.5, 1 and 4 postdose 3 days Day 3: pre-dose. 0.5,1 and 4 postdose

Examination of PK data across these studies suggests that some of theplasma concentration data may be spurious. 75% of the concentrations inboth studies are below the level of quantification (BLQ).

In study KX01-AK-002, PK data are available on 84 subjects in Cohort 1treated once daily for 5 days, and 84 subjects in Cohort 2 treated oncedaily for 3 days, with 0.5 mg KX-01 over a 25 cm² dosing area on theface or scalp. Out of a total of 336 plasma samples analyzed from these84 subjects following 1 day of treatment, 15 samples (˜4%) were abovethe limit of quantification. Prior to the dose administered on Day 5 and8 of 84 (˜9%) subjects had quantifiable concentrations of KX-01. On Day5 of dosing, measurable plasma concentrations were detected in 42 out of84 subjects at 4 hours post-dose. All measurable plasma concentrationswere below 0.7 ng/mL except for three aberrant samples.

Two of the three aberrant PK samples had observed plasma concentrationsof 44 and 23 ng/mL occurring at 1 and 0.5 hours post-dose in twodifferent subjects on Day 5. These primary PK samples were re-analyzedwith comparable results. Analysis of the back-up PK samples resulted inconcentrations of 0.351 ng/mL and BLQ, respectively. These results aremore consistent with the KX-01 plasma concentration from the other 82subjects and the other samples obtained from these subjects. One PKsample from a subject had an apparent plasma concentration above 12,500ng/mL but the back-up sample had a plasma concentration of 30 ng/mL. Themost likely cause of these aberrant results is cross contamination andthe results do not represent real KX-01 plasma concentrations. All sitesin study KX01-AK-002 have been retrained on the proper collection,handling and storage of PK samples.

In summary, the PK results of these studies showed that after 5consecutive days of topical treatment with KX-01, low systemic exposure(less than 1 ng/mL) and limited drug accumulation was observed.

Example 4—KX-01 Phase 3 Study

A Phase 3, double-blind, vehicle-controlled, randomized, parallel group,multicenter, efficacy and safety study of KX2-391 in adult subjects withAK on the face or scalp will be conducted at approximately 25 sites inthe United States, in order to study the following:

-   -   the efficacy of topical administration of KX-01 daily for 5        consecutive days compared to vehicle control in terms of 100%        clearance at Day 57 in the treatment of adults with actinic        keratosis (AK), when applied to a contiguous area of 25 cm² on        the face or scalp    -   the safety of topical KX-01 daily for 5 consecutive days in        terms of local skin reactions (LSRs) and other safety        evaluations such as adverse events (AEs) and laboratory        assessments    -   the rates of partial responders defined as at least 75%        clearance of AK lesions in the treatment area on the face or        scalp at Day 57 between the KX-01-treated group and        vehicle-treated group

Topical treatment with KX-daily for 5 consecutive days will demonstratea greater complete clearance (defined as 100% clearance of clinicallytypical and visible AK lesions at Day 57) than vehicle daily for 5consecutive days in adults with actinic keratosis on the face or scalp.

Enrollment will be controlled so that approximately two thirds ofsubjects enrolled will be treated on the face and approximately onethird of subjects enrolled will be treated on the scalp. Eligiblesubjects will be randomized centrally to treatment in a 1:1 (KX-01 orvehicle) ratio in each treatment area subgroup. That is to say, ineither the face or scalp-treated subject subgroup, half of the subjectswill receive the active study treatment randomly and the other half willreceive vehicle control randomly.

The treatment area will be marked with indelible marker on Day 1 at theinvestigational sites. Subjects will be provided with daily single-doseunits to be administered at home for 5 consecutive days. Subjects inboth groups will be instructed to wash their hands and the treatmentarea, then dry the treatment area before application of KX-01. A smallamount of KX-01 is to be applied to the fingertip and rubbed gently overthe entire treatment area of 25 cm². Subjects will be instructed to washtheir hands after applying the KX-01 and avoid washing the treatmentarea for at least 8 hours, and to avoid getting the KX-01 in the eyes.Subjects will return for follow-up for safety, LSR, and activity (AKlesion counts) evaluations at pre-specified time points until Day 57.All subjects who have unresolved LSRs, hypo- or hyper-pigmentation,scarring, or treatment-related AEs at Day 57 will return for post-studyfollow-up every 7-28 days until resolution or deemed stabilized by theInvestigators. Subjects who achieve 100% clearance of AK lesions in thetreatment area at Day 57 will be invited to enroll in an extensionprotocol to determine recurrence rate and safety for up to 12 months.

A sufficient number of subjects will be screened to randomizeapproximately 300 subjects. At each site, a minimum of 10 subjects and amaximum of 20 subjects will be randomized.

Each subject will be in the study for up to 85 days: screening up to 28days prior to day 1, treatment for 5 consecutive days, and follow-upuntil day 57. Use of any non-study drug treatment for AK lesions on thetreatment area is prohibited until Day 57.

Inclusion Criteria

-   1. Males and females ≥18 years old-   2. A treatment area on the face or scalp that:    -   is a contiguous area measuring 25 cm²    -   contains 4 to 8 clinically typical, visible and discrete AK        lesions-   3. Subjects who in the judgment of the Investigator, are in good    general health based on:    -   medical history    -   physical examination (PE) findings    -   electrocardiogram (ECG), clinical chemistry, hematology, and        urinalysis results-   4. Females must be postmenopausal (>45 years of age with at least 12    months of amenorrhea), surgically sterile (by hysterectomy,    bilateral oophorectomy, or tubal ligation); or, if of childbearing    potential, must be using highly effective contraception for at least    30 days or 1 menstrual cycle, whichever is longer, prior to    treatment with KX01 and must agree to continue to use highly    effective contraception for at least 30 days following their last    dose of KX01. Highly effective contraception includes oral hormonal    contraceptives, hormonal contraceptive implant, injection or patch,    intrauterine device or complete abstinence from sexual intercourse    for 2 weeks before dosing and throughout the study.-   5. Males who have not had a vasectomy must agree to use barrier    contraception from Screening through 90 days after their last dose    of KX-01.-   6. All subjects must agree not to donate sperm or eggs or attempt    conception from Screening through 90 days following their last dose    of KX-01.-   7. Females of childbearing potential must have a negative serum    pregnancy test at Screening and a negative urine pregnancy test on    Day 1 prior to administration of study treatment.-   8. Willing to avoid direct sun or ultraviolet (UV) light exposure to    the face or scalp-   9. Able to comprehend and are willing to sign an informed consent    form (ICF)

Exclusion Criteria

-   1. Clinically atypical and/or rapidly changing AK lesions on the    treatment area, e.g., hypertrophic, hyperkeratotic, recalcitrant    disease (had cryosurgery on two previous occasions) and/or cutaneous    horn-   2. Location of the treatment area:    -   On any location other than the face or scalp    -   Within 5 cm of an incompletely healed wound    -   Within 5 cm of a suspected basal cell carcinoma (BCC) or        squamous cell carcinoma (SCC)-   3. Been previously treated with KX-01-   4. Anticipated need for in-patient hospitalization or in-patient    surgery-   5. Treatment with 5-fluorouracil (5-FU), imiquimod, ingenol    mebutate, diclofenac, photodynamic therapy, or other treatments for    AK within 2 cm of the treatment area, within 8 weeks prior to the    Screening visit-   6. Use of the following therapies and/or medications within 2 weeks    prior to the Screening visit:    -   Cosmetic or therapeutic procedures (e.g., use of liquid        nitrogen, surgical excision, curettage, dermabrasion, medium or        greater depth chemical peel, laser resurfacing) within 2 cm of        the selected treatment area    -   Acid-containing therapeutic products (e.g., salicylic acid or        fruit acids, such as alpha- and beta-hydroxyl acids and glycolic        acids), topical retinoids, or light chemical peels within 2 cm        of the selected treatment area    -   Topical salves (non-medicated/non-irritant lotion and cream are        acceptable) or topical steroids within 2 cm of the selected        treatment area; artificial tanners within 5 cm of the selected        treatment area-   7. Use of the following therapies and/or medications within 4 weeks    prior to the Screening visit:    -   Treatment with immunomodulators (e.g., azathioprine), cytotoxic        drugs (e.g., cyclophosphamide, vinblastine, chlorambucil,        methotrexate) or interferons/interferon inducers    -   Treatment with systemic medications that suppress the immune        system (e.g., cyclosporine, prednisone, methotrexate, alefacept,        infliximab)    -   Treatment/therapy with UVA or UVB-   8. Use of systemic retinoids (e.g., isotretinoin, acitretin,    bexarotene) within 6 months prior to the Screening visit-   9. A history of sensitivity and/or allergy to any of the ingredients    in the study medication-   10. A skin disease (e.g., atopic dermatitis, psoriasis, eczema) or    condition (e.g., scarring, open wounds) that, in the opinion of the    Investigator, might interfere with the study conduct or evaluations,    or which exposes the subject to unacceptable risk by study    participation-   11. Other significant uncontrolled or unstable medical diseases or    conditions that, in the opinion of the Investigator, would expose    the subject to unacceptable risk by study participation-   12. Females who are pregnant or nursing-   13. Participated in an investigational drug trial during which an    investigational study medication was administered within 30 days or    5 half-lives of the investigational product, whichever is longer,    before dosing

Activity Assessments

The Investigator or designee will perform a count of AK lesions in thetreatment area for all subjects at Screening and on days 1 (Baseline),8, 15, 29, and 57.

Safety Assessments

Safety will be assessed on days 1 (Baseline), 6, 8, 15, 29, and 57 byrecording LSRs, AEs, and serious adverse events (SAEs).

Laboratory evaluation of hematology, biochemistry, and urinalysisvalues, measurement of weight, height, and vital signs, evaluation ofECGs, and PEs will be conducted at pre-specified time points.

Subjects will be queried for spontaneously reported AEs at each studyvisit, before assessment of LSRs. AEs will be reported separately fromLSRs.

Other Assessments

The LSR assessment is the Investigator's (or trained designee's)assessment of the following signs on the treatment area: erythema,flaking/scaling, crusting, swelling, vesiculation/pustulation, anderosion/ulceration. These signs will be assessed using a grading scaleranging from 0=absent, 1=mild (slightly, barely perceptible), 2=moderate(distinct presence), and 3=severe (marked, intense).

In addition to LSRs, hypo- and hyper-pigmentation and scarring on thetreatment area will be assessed as being present or absent. Applicationsite reactions not classified as LSRs (e.g., pruritus, pain, infection)will be reported as adverse events. Investigators will be trained in theuse of this LSR scale using representative photographs. Standardizedphotography will be performed on Day 1 prior to dosing, and on days 6,8, 15, 29, and 57.

The primary efficacy endpoint is the complete clearance rate of AKlesions, defined as the proportion of subjects at Day 57 with noclinically visible AK lesions in the treatment area. The secondaryefficacy endpoint is partial clearance rate of AK lesions defined as theproportion of subjects at Day 57 with a 75% or greater reduction in thenumber of AK lesions identified at Day 1 (Baseline) in the treatmentarea. Reduction in AK lesion counts during Days 1-57 will also beexamined.

Safety endpoints includes evaluation of LSRs, pigmentation and scarring,AEs, SAEs, events of special interests, and clinical laboratory data;the results of other safety assessments (vital signs, PEs, ECGs) willalso be evaluated.

The patient populations includes (1) Intent-To-Treat (ITT)/SafetyPopulation: all randomized subjects who have received at least one dayof treatment and returned for a follow-up visit and (2) Per-Protocol(PP)/Evaluable Population: all randomized subjects who have received atleast 4 of the 5 doses, conformed to the protocol as to entry criteria,did not receive concomitant medications that can affect efficacy, andreturned for the final visit at Day 57. This is the primary efficacypopulation.

The primary efficacy endpoint, complete clearance rate, will be comparedbased on a Cochran-Mantel-Haenszel (CMH) method controlling fortreatment areas (face or scalp) between treatment groups. In addition,complete clearance rate comparison between treatment groups will beperformed in the face and scalp-treated subgroups independently. Partialclearance rate will be analyzed in the same way as the primary efficacyendpoint (complete clearance rate).

To indicate concordance with the overall results, complete clearancerate will also be tabulated and displayed graphically as well in suchsubgroups as gender, age (<65 or ≥65 years), study site, baseline lesioncount (4, 5, 6 or 7, 8), skin type (Fitzpatrick I/II or III/IV/V/VI).Outliers will be clinically explained in the clinical study report.

The number of AK lesions at Baseline, Day 57, and other visits andchanges from baseline in the number of AK lesions at each visit will besummarized using descriptive statistics (i.e., mean, standard deviation,median, minimum and maximum), and then contrasted for each treatmentgroup.

Safety analyses will be performed in the Safety Population.

Treatment-emergent AEs (TEAEs) are defined as either those AEs with anonset after dosing or those pre-existing AEs that worsen after dosing.For AEs, verbatim terms on the case report form/electronic case reportform (CRF/eCRF) will be mapped to preferred terms (PTs) and system organclasses (SOCs) using the Medical Dictionary for Regulatory Activities(MedDRA; v 16.0 or higher). Subject incidence of AEs will be displayedby SOC. The incidence of TEAEs will be summarized by treatment group.TEAEs will also be summarized by severity, relationship to studytreatment, and treatment group. Subject incidence of SAEs will also bedisplayed by treatment group. Laboratory parameters will be summarizedusing descriptive statistics at baseline and at each subsequenttimepoint by treatment group. Changes from baseline will also besummarized by treatment group. In addition, shift tables (i.e.,low-normal-high at baseline versus low-normal-high at follow-up in a3-by-3 contingency table) will be provided to assess changes inlaboratory values from baseline to follow-up in each treatment group.Local skin reactions, pigmentation, and scarring as reported by theInvestigator, will be displayed and summarized by visit and treatmentgroup for all subjects. Events of special interest will be summarized.

Example 5—KX-01 Phase 3 Extension Study Protocol Synopsis (RecurrenceFollow up Protocol)

A 12-month prospective, longitudinal, follow-up study of completeresponders from two Phase 3 studies of KX-01 administered topically inadult subjects with AK on the Face or Scalp will be conducted atapproximately 25 sites in the United States, in order to determine therecurrence of actinic keratosis (AK) in the treatment area of subjectswho had complete clearance at Day 57 in the Phase 3 studies of KX-01 andto study adverse events (AEs) in the treatment area.

Eligibility Criteria

-   1. Complete clearance defined as 100% clearance of AK lesions in the    treatment area on Day 57 in subjects from the two Phase 3 studies-   2. Willing to avoid direct sun or ultraviolet (UV) light exposure to    the face or scalp-   3. Able to comprehend and are willing to comply with study    procedures and sign an informed consent form (ICF)

No subject will be re-treated with the study drug. Subjects will beprohibited from receiving field treatment or treatment that may mask theincidence of AK lesion recurrence (e.g., topical ingenol mebutate,5-fluorouracil [5-FU], diclofenac, imiquimod) inside or within 2 cm ofthe treatment area at any time during the study. Isolated lesiontreatment, such as cryotherapy or biopsy, will be allowed for treatmentof AK lesions emerging in the selected treatment area. Clinic visitswill occur at months 3, 6, 9, and 12 after the day 57 visit of thefeeder Phase 3 studies. The number of AK lesions in the treatment areawill be counted at each visit. If a subject receives lesion-specifictreatment (i.e., cryotherapy or biopsy) for a lesion that appears in thetreatment area, the treated lesion will be considered a recurrence.Information regarding intercurrent disorders, therapeutics that mayresult in immunosuppression, and treatment with agents known to alter AKwill be collected. Adverse events and serious adverse events (SAEs),including skin cancers (basal cell carcinoma [BCC]/squamous cellcarcinoma [SCC]/melanoma) in the treatment area or within 5 cm of thetreatment area border will be reported. Other AEs and SAEs will bereported if they are considered by the Investigator to be related tostudy treatment. Standard photography will be performed at all visits.

For efficacy, the recurrence of AK lesion will be evaluated, which isdefined as any identified AK lesion in the selected treatment areaduring the 12-month follow-up period for subjects who achieved completeclearance at the day 57 visit of the Phase 3 studies, regardless of thetreatments they received previously. If a subject receiveslesion-specific treatment (i.e., cryotherapy or biopsy) for a lesionthat appears in the treatment area, the treated lesion is considered arecurrence.

For safety, AEs in the selected treatment area will be evaluated duringthe 12-month follow-up period. Other AEs which are reported by theinvestigators as being treatment-related will be evaluated as well.

The analysis population includes all subjects who achieved completeclearance at the day 57 visit of the feeder Phase 3 studies, regardlessof which treatments they received previously. Both efficacy and safetyanalyses will be performed based on this population.

Analysis results by previous treatment groups (active treatment vsvehicle control) will be mainly contrasted by tabulations and graphs.The Kaplan-Meier method-based recurrence rate with a 95% confidenceinterval (CI) will be estimated at scheduled post-baseline visits (3, 6,9, and 12 months) by previous treatment. The time when lesion(s) is/areobserved will be imputed to the corresponding target study day (e.g., 91days for the 3-month visit). The Kaplan-Meier method-based recurrencerate with a 95% confidence interval (CI) will be estimated at scheduledpost-baseline visits (3, 6, 9, and 12 months) by previous treatment. Thetime when lesion(s) is/are observed will be imputed to the correspondingtarget study day (e.g., 91 days for the 3-month visit).

In addition, the Kaplan-Meier method-based median time to recurrence(i.e., appearance of a new or recurrent lesion in the treatment area)will be displayed graphically by previous treatment. The number of AKlesion counts in the treatment area will be summarized at each scheduledpost-baseline visit by previous treatment. Furthermore, the number oflesions in the treatment area normalized by corresponding baselinelesion counts from the Phase 3 studies (expressed as percentages) willbe summarized at each scheduled post-baseline visit by previoustreatment.

For AEs that are collected in the treatment area, verbatim terms on thecase report form/electronic case report form (CRF/eCRF) will be mappedto preferred terms (PTs) and system organ classes (SOCs) using theMedical Dictionary for Regulatory Activities (MedDRA; v 16.0 or higher).Subject incidence of AEs will be displayed by SOC and PT. The incidenceof AEs will be summarized by previous treatment. Subject incidence ofSAEs will be displayed by previous treatment. Adverse events that arereported by the Investigators as being treatment-related will beevaluated in the same way, but separately.

Example 6—Comparison of Skin Reaction with KX-01 Compared with Picato(Ingenol Mebutate)®, the Standard of Care Treatment of AK

Initial data from the patients in the studies described herein (e.g.,Example 1 and Examples 2a and 2b) demonstrate that the efficacy of KX-01for clearing AK lesions may be similar to Picato (Ingenol Mebutate)®,the approved therapy for AK. Additionally, treatment with KX-01 resultsin fewer and less severe skin reactions in the subject, i.e., less skintoxicity, compared to Picato (Ingenol Mebutate)®.

This is illustrated in FIGS. 3A and 3B, which demonstrate the skinreaction in the forearm of subject at day 3 and day 5 of treatment withPicato (Ingenol Mebutate)®, which shows severe skin reactions (FIG. 3A).Comparatively, the forearm of subject at day 3 and day 5 of treatmentwith KX-01, in a subject who had a 100% response to KX-01 topicaltreatment, exhibits minimal or no adverse skin reactions (FIG. 3B).

Similarly, FIGS. 4A and 4B illustrate the adverse skin reaction in theforehead of a subject at day 4 and day 15 of treatment with Picato(Ingenol Mebutate)®, which shows severe skin reactions (FIG. 4A).Comparatively, the forehead of a subject at day 8 and day 57 oftreatment with KX-01, in a subject who had a 100% response to KX-01topical treatment, also exhibits minimal or no adverse skin reactions(FIG. 4B).

The comparison in FIGS. 3A, 3B, 4A, and 4B illustrates the lack of skintoxicity observed in the treatment of AK with topically administeredKX-01 compared to the approved therapy for AK. This is likely to be asignificant consideration of clinicians and patients, and, to the extentthat skin toxicity has been limiting to the market of current treatmentoptions for subjects suffering from AK, KX-01 may significantly expandthe market as a result of less skin toxicity.

EQUIVALENTS

The disclosure of the application can be embodied in other specificforms without departing from the spirit or essential characteristicsthereof. The foregoing embodiments are therefore to be considered in allrespects illustrative rather than limiting on the disclosure of theapplication described herein. Scope of the disclosure of the applicationis thus indicated by the appended claims rather than by the foregoingdescription, and all changes that come within the meaning and range ofequivalency of the claims are intended to be embraced therein.

1. A method of treating and/or preventing actinic keratosis comprisingadministering to a subject in need thereof a therapeutically effectiveamount of KX-01:


2. The method of claim 1, wherein KX-01 is administered to an affectedarea of the subject at a dose from about 0.1 mg to about 10 mg, fromabout 0.2 mg to about 5 mg, or from about 0.5 mg to about 2.5 mg.
 3. Themethod of claim 1, wherein KX-01 is administered to an affected area ofthe subject at a dose of about 0.2 mg, about 0.3 mg, about 0.4 mg, about0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg,about 4 mg, or about 5 mg.
 4. The method of claim 1, wherein KX-01 isadministered to an affected area of the subject at a dose from about0.0003 mg/cm² to about 10 mg/cm², from about 0.001 mg/cm² to about 0.4mg/cm², from about 0.005 mg/cm² to about 0.1 mg/cm², from about 0.005mg/cm² to about 0.02 mg/cm², or from about 0.025 mg/cm² to about 0.1mg/cm².
 5. The method of claim 1, wherein KX-01 is administered to anaffected area of the subject at a dose of about 0.001 mg/cm², about0.002 mg/cm², about 0.003 mg/cm², about 0.004 mg/cm², about 0.005mg/cm², about 0.006 mg/cm², about 0.007 mg/cm², about 0.008 mg/cm²,about 0.009 mg/cm², about 0.01 mg/cm², about 0.02 mg/cm², about 0.03mg/cm², about 0.04 mg/cm², about 0.05 mg/cm², about 0.06 mg/cm², about0.07 mg/cm², about 0.08 mg/cm², about 0.09 mg/cm², about 0.1 mg/cm²,about 0.15 mg/cm², about 0.2 mg/cm², about 0.25 mg/cm², about 0.3mg/cm², about 0.35 mg/cm², or about 0.4 mg/cm².
 6. The method of claim2, wherein the affected area is about 0.01 cm² to about 300 cm², about 1cm² to about 200 cm², about 1 cm² to about 100 cm², about 1 cm² to about75 cm², about 1 cm² to about 50 cm², about 1 cm² to about 25 cm², about10 cm² to about 200 cm², about 10 cm² to about 100 cm², about 10 cm² toabout 75 cm², about 10 cm² to about 50 cm², about 10 cm² to about 25cm², about 25 cm² to about 200 cm², about 25 cm² to about 100 cm², about25 cm² to about 75 cm², or about 25 cm² to about 50 cm², about 25 cm² toabout 90 cm², about 25 cm² to about 80 cm², or about 25 cm² to about 70cm², about 25 cm² to about 60 cm², about 25 cm² to about 40 cm², orabout 25 cm² to about 30 cm².
 7. The method of claim 2, wherein theaffected area is about 25 cm², about 30 cm², about 35 cm², about 40 cm²,about 45 cm², about 50 cm², about 55 cm², about 60 cm², about 65 cm²,about 70 cm², about 75 cm², about 80 cm², about 85 cm², about 90 cm²,about 95 cm², or about 100 cm².
 8. The method of claim 2, wherein theaffected area is the skin.
 9. The method of claim 1, wherein KX-01 isadministered once a week, once every three days, once every two days,once a day, twice a day, three times a day, or four times a day.
 10. Themethod of claim 1, wherein KX-01 is administered for 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 days.
 11. Themethod of claim 1, wherein KX-01 is administered for 1, 2, 3, 4 or 5days.
 12. The method of claim 1, wherein KX-01 is administered for 1, 2,3, 4, 5, or 6 days per week.
 13. The method of claim 1, wherein KX-01 isadministered once or twice daily continuously for more than one day perweek, followed by discontinuation of the administration for the rest ofthe week.
 14. The method of claim 1, wherein KX-01 is administered onceor twice daily every other day, every three days, every four days, everyfive days, every six days, or every seven days.
 15. The method of claim1, wherein KX-01 is administered once or twice daily for two days in arow every three days, every four days, every five days, every six days,or every seven days.
 16. The method of claim 1, wherein KX-01 isadministered once or twice daily for three days in a row every fourdays, every five days, every six days, or every seven days.
 17. Themethod of claim 1, wherein KX-01 is administered once or twice daily forfour days in a row every five days, every six days, or every seven days.18. The method of claim 1, wherein KX-01 is administered until theactinic keratosis is fully treated.
 19. The method of claim 1, whereinKX-01 is administered topically.
 20. The method of claim 1, wherein theadministration of KX-01 reduces the number and/or severity of, or thenumber of the subjects that have, local skin reactions or other adverseside effects in the subject compared to other treatments of actinickeratosis.